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Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer (STEAM)

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ClinicalTrials.gov Identifier: NCT01765582
Recruitment Status : Terminated
First Posted : January 10, 2013
Results First Posted : September 18, 2017
Last Update Posted : September 18, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Neoplasms
Interventions Drug: 5-fluorouracil
Drug: bevacizumab
Drug: capecitabine
Drug: irinotecan
Drug: folinic acid
Drug: oxaliplatin
Enrollment 280
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab
Hide Arm/Group Description Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Period Title: Overall Study
Started 93 92 95
Completed 0 0 0
Not Completed 93 92 95
Reason Not Completed
Other             3             6             9
Lost to Follow-up             2             2             1
Death             31             36             33
Sponsor Decision             46             42             42
Withdrawal of Consent             11             6             10
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Total
Hide Arm/Group Description Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Total of all reporting groups
Overall Number of Baseline Participants 93 92 95 280
Hide Baseline Analysis Population Description
Intent to Treat (ITT) population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 93 participants 92 participants 95 participants 280 participants
56.0  (11.53) 56.0  (10.46) 57.9  (9.86) 56.7  (10.63)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 93 participants 92 participants 95 participants 280 participants
Female
42
  45.2%
40
  43.5%
36
  37.9%
118
  42.1%
Male
51
  54.8%
52
  56.5%
59
  62.1%
162
  57.9%
1.Primary Outcome
Title Percentage of Participants With Overall Response During First-Line Therapy (ORR1)
Hide Description ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to <10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR
Time Frame Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 93 92 95 185
Measure Type: Number
Unit of Measure: Percentage of participants
72.0 72.8 62.1 72.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Concurrent FOLFOXIRI + Bevacizumab, Arm C: FOLFOX + Bevacizumab
Comments Stratified by extent of metastatic disease (liver-limited disease versus non liver-limited disease) and tumor location (right versus left) after correction post-randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.132
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.62
Confidence Interval (2-Sided) 90%
0.96 to 2.71
Estimation Comments [Not Specified]
2.Primary Outcome
Title Progression-Free Survival During First-Line Therapy (PFS1)
Hide Description PFS1 was defined as time from randomization to the first occurrence of disease progression during first-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5 mm.
Time Frame Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 93 92 95 185
Median (90% Confidence Interval)
Unit of Measure: months
11.86
(9.95 to 16.62)
11.37
(9.20 to 13.34)
9.46
(8.08 to 11.20)
11.70
(10.35 to 13.34)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm C: FOLFOX + Bevacizumab, Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Comments Stratified by extent of metastatic disease (liver-limited disease vs. non-liver-limited disease) and tumor location (right vs. left) after correction post-randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.68
Confidence Interval (2-Sided) 90%
0.53 to 0.88
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time to PFS2
Hide Description Time to PFS2 was defined as time from randomization to the first occurrence of disease progression after reinduction of second-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5mm.
Time Frame Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 24 30 29 54
Median (90% Confidence Interval)
Unit of Measure: months
18.76
(13.63 to 24.31)
13.17
(10.61 to 16.82)
14.75
(11.01 to 16.13)
15.08
(13.17 to 18.53)
4.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from the date of randomization to the date of death from any cause.
Time Frame Randomization until death due to any cause (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 93 92 95 185
Median (90% Confidence Interval)
Unit of Measure: months
33.97
(23.69 to 33.97)
28.32 [1] 
(22.21 to NA)
30.65
(25.17 to 30.65)
28.32 [2] 
(23.75 to NA)
[1]
N/A = NE = not evaluable: The value cannot be estimated because the curve representing the upper confidence limits for the survivor function lies above 0.5.
[2]
N/A = NE = not evaluable:The value cannot be estimated because the curve representing the upper confidence limits for the survivor function lies above 0.5.
5.Secondary Outcome
Title Proportion of Participants Who Underwent Liver Metastases Resections
Hide Description Reported here is the proportion of participants who underwent liver metastases resections calculated as follows: number of participants who underwent liver metastases resections divided by total number of participants in each arm.
Time Frame Randomization up to approximately 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 93 92 95 185
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Proportion of participants
0.17
(0.11 to 0.24)
0.10
(0.05 to 0.15)
0.08
(0.04 to 0.13)
0.14
(0.09 to 0.18)
6.Secondary Outcome
Title Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases
Hide Description The proportion of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases was calculated as follows: number of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases divided by total number of participants in each arm. This outcome represents a measure of the rate of conversion from unresectable to resectable disease.
Time Frame Randomization up to approximately 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population was defined as all randomized participants regardless of whether they received any dose of study treatment.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 93 92 95 185
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Proportion of participants
0.24
(0.16 to 0.31)
0.17
(0.11 to 0.24)
0.14
(0.08 to 0.19)
0.21
(0.16 to 0.25)
7.Secondary Outcome
Title Percentage of Participants With Adverse Events
Hide Description An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time Frame Randomization up to approximately 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab Arms A + B: Pooled FOLFOXIRI + Bevacizumab
Hide Arm/Group Description:
Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
This analysis set combines Arms A and B and represents participants who received either concurrent or sequential FOLFOXIRI with 5 mg/kg of bevacizumab during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
Overall Number of Participants Analyzed 91 90 90 181
Measure Type: Number
Unit of Measure: Percentage of participants
100 98.9 100 99.4
Time Frame From baseline up to approximately 3 years.
Adverse Event Reporting Description Safety population was defined as all randomized participants who received at least one partial or complete dose of study medication.
 
Arm/Group Title Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab
Hide Arm/Group Description Participants received concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-fluorouracil (5-FU) with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Participants received alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion. Participants received FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibited good response and tolerated the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) was administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.
All-Cause Mortality
Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   39/91 (42.86%)   42/90 (46.67%)   43/90 (47.78%) 
Blood and lymphatic system disorders       
Febrile neutropenia  1  2/91 (2.20%)  2/90 (2.22%)  2/90 (2.22%) 
Neutropenia  1  2/91 (2.20%)  2/90 (2.22%)  0/90 (0.00%) 
Leukopenia  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Thrombocytopenia  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Cardiac disorders       
Acute myocardial infarction  1  1/91 (1.10%)  0/90 (0.00%)  1/90 (1.11%) 
Myocardial infarction  1  0/91 (0.00%)  2/90 (2.22%)  0/90 (0.00%) 
Arteriospasm coronary  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Cardiac arrest  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Supraventricular tachycardia  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Gastrointestinal disorders       
Diarrhoea  1  5/91 (5.49%)  1/90 (1.11%)  5/90 (5.56%) 
Abdominal pain  1  3/91 (3.30%)  0/90 (0.00%)  5/90 (5.56%) 
Constipation  1  1/91 (1.10%)  1/90 (1.11%)  2/90 (2.22%) 
Gastrointestinal haemorrhage  1  1/91 (1.10%)  0/90 (0.00%)  3/90 (3.33%) 
Anal fistula  1  0/91 (0.00%)  1/90 (1.11%)  1/90 (1.11%) 
Ascites  1  2/91 (2.20%)  0/90 (0.00%)  0/90 (0.00%) 
Colitis  1  1/91 (1.10%)  1/90 (1.11%)  0/90 (0.00%) 
Abdominal pain upper  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Anal fissure  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Duodenal ulcer  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Small intestinal obstruction  1  2/91 (2.20%)  3/90 (3.33%)  5/90 (5.56%) 
Vomiting  1  3/91 (3.30%)  0/90 (0.00%)  4/90 (4.44%) 
Large intestine perforation  1  2/91 (2.20%)  3/90 (3.33%)  1/90 (1.11%) 
Nausea  1  3/91 (3.30%)  0/90 (0.00%)  0/90 (0.00%) 
Large intestinal obstruction  1  2/91 (2.20%)  0/90 (0.00%)  0/90 (0.00%) 
Rectal perforation  1  1/91 (1.10%)  0/90 (0.00%)  1/90 (1.11%) 
Rectal Haemorrhage  1  1/91 (1.10%)  1/90 (1.11%)  0/90 (0.00%) 
Gastrointestinal perforation  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Ileus  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Intestinal perforation  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Large intestinal stenosis  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Lower gastrointestinal haemorrhage  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Obstruction gastric  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Rectal obstruction  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Intestinal obstruction  1  1/91 (1.10%)  2/90 (2.22%)  1/90 (1.11%) 
General disorders       
Death  1  1/91 (1.10%)  1/90 (1.11%)  0/90 (0.00%) 
Pyrexia  1  2/91 (2.20%)  0/90 (0.00%)  0/90 (0.00%) 
Asthenia  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Chest pain  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Fatigue  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
General physical health deterioration  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Medical device pain  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Mucosal inflammation  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Non-cardiac chest pain  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Hepatobiliary disorders       
Cholelithiasis  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Hepatic failure  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Hepatic haemorrhage  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Jaundice cholestatic  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Infections and infestations       
Pneumonia  1  1/91 (1.10%)  5/90 (5.56%)  1/90 (1.11%) 
Sepsis  1  1/91 (1.10%)  2/90 (2.22%)  4/90 (4.44%) 
Abdominal abscess  1  0/91 (0.00%)  0/90 (0.00%)  3/90 (3.33%) 
Urinary tract infection  1  1/91 (1.10%)  1/90 (1.11%)  1/90 (1.11%) 
Clostridium difficile colitis  1  1/91 (1.10%)  1/90 (1.11%)  0/90 (0.00%) 
Gastroenteritis  1  0/91 (0.00%)  1/90 (1.11%)  1/90 (1.11%) 
Subcutaneous abscess  1  0/91 (0.00%)  1/90 (1.11%)  1/90 (1.11%) 
Appendicitis  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Bacterial infection  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Carbuncle  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Device related infection  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Diverticulitis  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Enterocolitis infectious  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Gastroenteritis viral  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Liver abscess  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Necrotising fasciitis  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Neutropenic sepsis  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Pelvic abscess  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Pneumococcal sepsis  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Rectal abscess  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Septic shock  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Stoma site infection  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Urinary tract infection bacterial  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Urosepsis  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Wound infection  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Injury, poisoning and procedural complications       
Accidental overdose  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Cystitis radiation  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Fall  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Femoral neck fracture  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Infusion related reaction  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Postoperative respiratory failure  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Procedural complication  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Stoma obstruction  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Stoma site pain  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Subdural haematoma  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Thoracic vertebral fracture  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Investigations       
Neutrophil count decreased  1  2/91 (2.20%)  0/90 (0.00%)  1/90 (1.11%) 
Blood bilirubin increased  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Metabolism and nutrition disorders       
Dehydration  1  6/91 (6.59%)  2/90 (2.22%)  3/90 (3.33%) 
Hypokalaemia  1  2/91 (2.20%)  1/90 (1.11%)  0/90 (0.00%) 
Hyperglycaemia  1  0/91 (0.00%)  0/90 (0.00%)  2/90 (2.22%) 
Electrolyte imbalance  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Failure to thrive  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Hyponatraemia  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Lactic acidosis  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  1/91 (1.10%)  1/90 (1.11%)  1/90 (1.11%) 
Muscular weakness  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Pathological fracture  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Soft tissue necrosis  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Synovitis  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Tumour compression  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Nervous system disorders       
Syncope  1  1/91 (1.10%)  0/90 (0.00%)  2/90 (2.22%) 
Central nervous system lesion  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Cerebrovascular accident  1  1/91 (1.10%)  0/90 (0.00%)  0/90 (0.00%) 
Embolic stroke  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Encephalopathy  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Headache  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Metabolic encephalopathy  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Spinal cord compression  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Subarachnoid haemorrhage  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Psychiatric disorders       
Mental status changes  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Renal and urinary disorders       
Acute kidney injury  1  0/91 (0.00%)  2/90 (2.22%)  0/90 (0.00%) 
Acute prerenal failure  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Nephrolithiasis  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Urinary bladder rupture  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Pulmonary embolism  1  3/91 (3.30%)  5/90 (5.56%)  4/90 (4.44%) 
Acute respiratory distress syndrome  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Asthma  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Dyspnoea  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Laryngeal oedema  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Skin and subcutaneous tissue disorders       
Palmar-plantar erythrodysaesthesia syndrome  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Skin ulcer  1  0/91 (0.00%)  1/90 (1.11%)  0/90 (0.00%) 
Surgical and medical procedures       
Wound drainage  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Vascular disorders       
Deep vein thrombosis  1  1/91 (1.10%)  1/90 (1.11%)  1/90 (1.11%) 
Air embolism  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Hypotension  1  0/91 (0.00%)  0/90 (0.00%)  1/90 (1.11%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Arm A: Concurrent FOLFOXIRI + Bevacizumab Arm B: Sequential FOLFOXIRI + Bevacizumab Arm C: FOLFOX + Bevacizumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   91/91 (100.00%)   89/90 (98.89%)   89/90 (98.89%) 
Blood and lymphatic system disorders       
Neutropenia  1  42/91 (46.15%)  43/90 (47.78%)  29/90 (32.22%) 
Anaemia  1  16/91 (17.58%)  17/90 (18.89%)  24/90 (26.67%) 
Thrombocytopenia  1  9/91 (9.89%)  12/90 (13.33%)  9/90 (10.00%) 
Ear and labyrinth disorders       
Ear pain  1  1/91 (1.10%)  2/90 (2.22%)  5/90 (5.56%) 
Eye disorders       
Vision blurred  1  17/91 (18.68%)  9/90 (10.00%)  7/90 (7.78%) 
Lacrimation increased  1  4/91 (4.40%)  8/90 (8.89%)  7/90 (7.78%) 
Gastrointestinal disorders       
Diarrhoea  1  73/91 (80.22%)  65/90 (72.22%)  49/90 (54.44%) 
Constipation  1  28/91 (30.77%)  45/90 (50.00%)  41/90 (45.56%) 
Abdominal pain  1  35/91 (38.46%)  30/90 (33.33%)  28/90 (31.11%) 
Dyspepsia  1  8/91 (8.79%)  15/90 (16.67%)  10/90 (11.11%) 
Abdominal pain upper  1  9/91 (9.89%)  14/90 (15.56%)  3/90 (3.33%) 
Flatulence  1  12/91 (13.19%)  7/90 (7.78%)  6/90 (6.67%) 
Gastrooesophageal reflux disease  1  5/91 (5.49%)  11/90 (12.22%)  9/90 (10.00%) 
Abdominal distention  1  5/91 (5.49%)  6/90 (6.67%)  9/90 (10.00%) 
Haematochezia  1  8/91 (8.79%)  3/90 (3.33%)  5/90 (5.56%) 
Ascites  1  3/91 (3.30%)  4/90 (4.44%)  5/90 (5.56%) 
Dry mouth  1  6/91 (6.59%)  4/90 (4.44%)  2/90 (2.22%) 
Dysphagia  1  2/91 (2.20%)  6/90 (6.67%)  0/90 (0.00%) 
Nausea  1  59/91 (64.84%)  64/90 (71.11%)  53/90 (58.89%) 
Vomiting  1  33/91 (36.26%)  36/90 (40.00%)  24/90 (26.67%) 
Stomatitis  1  31/91 (34.07%)  36/90 (40.00%)  25/90 (27.78%) 
Haemorrhoids  1  7/91 (7.69%)  11/90 (12.22%)  12/90 (13.33%) 
Rectal haemorrhage  1  11/91 (12.09%)  9/90 (10.00%)  6/90 (6.67%) 
Oral pain  1  10/91 (10.99%)  6/90 (6.67%)  8/90 (8.89%) 
Proctalgia  1  8/91 (8.79%)  4/90 (4.44%)  5/90 (5.56%) 
General disorders       
Fatigue  1  68/91 (74.73%)  68/90 (75.56%)  60/90 (66.67%) 
Temperature intolerance  1  26/91 (28.57%)  24/90 (26.67%)  25/90 (27.78%) 
Mucosal inflammation  1  16/91 (17.58%)  16/90 (17.78%)  14/90 (15.56%) 
Pyrexia  1  16/91 (17.58%)  10/90 (11.11%)  15/90 (16.67%) 
Oedema peripheral  1  10/91 (10.99%)  11/90 (12.22%)  6/90 (6.67%) 
Chills  1  7/91 (7.69%)  7/90 (7.78%)  10/90 (11.11%) 
Pain  1  4/91 (4.40%)  11/90 (12.22%)  9/90 (10.00%) 
Asthenia  1  2/91 (2.20%)  7/90 (7.78%)  9/90 (10.00%) 
Chest pain  1  6/91 (6.59%)  4/90 (4.44%)  1/90 (1.11%) 
Peripheral swelling  1  6/91 (6.59%)  3/90 (3.33%)  2/90 (2.22%) 
Influenza like illness  1  3/91 (3.30%)  6/90 (6.67%)  1/90 (1.11%) 
Oedema  1  0/91 (0.00%)  6/90 (6.67%)  2/90 (2.22%) 
Immune system disorders       
Hypersensitivity  1  2/91 (2.20%)  2/90 (2.22%)  6/90 (6.67%) 
Infections and infestations       
Urinary tract infection  1  13/91 (14.29%)  16/90 (17.78%)  17/90 (18.89%) 
Upper respiratory tract infection  1  12/91 (13.19%)  11/90 (12.22%)  7/90 (7.78%) 
Sinusitis  1  6/91 (6.59%)  11/90 (12.22%)  2/90 (2.22%) 
Nasopharyngitis  1  4/91 (4.40%)  3/90 (3.33%)  6/90 (6.67%) 
Oral herpes  1  2/91 (2.20%)  6/90 (6.67%)  0/90 (0.00%) 
Injury, poisoning and procedural complications       
Infusion related reaction  1  13/91 (14.29%)  6/90 (6.67%)  2/90 (2.22%) 
Fall  1  5/91 (5.49%)  2/90 (2.22%)  6/90 (6.67%) 
Contusion  1  5/91 (5.49%)  3/90 (3.33%)  4/90 (4.44%) 
Investigations       
Weight decreased  1  17/91 (18.68%)  11/90 (12.22%)  20/90 (22.22%) 
Neutrophil count decreased  1  14/91 (15.38%)  12/90 (13.33%)  11/90 (12.22%) 
Aspartate aminotransferase increased  1  6/91 (6.59%)  7/90 (7.78%)  4/90 (4.44%) 
White blood cell count decreased  1  3/91 (3.30%)  8/90 (8.89%)  6/90 (6.67%) 
Blood alkaline phosphatase increased  1  6/91 (6.59%)  6/90 (6.67%)  3/90 (3.33%) 
Blood bilirubin increased  1  3/91 (3.30%)  2/90 (2.22%)  7/90 (7.78%) 
Platelet count decreased  1  4/91 (4.40%)  5/90 (5.56%)  2/90 (2.22%) 
Alanine aminotransferase increased  1  6/91 (6.59%)  5/90 (5.56%)  5/90 (5.56%) 
Metabolism and nutrition disorders       
Deceased appetite  1  38/91 (41.76%)  38/90 (42.22%)  34/90 (37.78%) 
Hypokalaemia  1  24/91 (26.37%)  17/90 (18.89%)  15/90 (16.67%) 
Dehydration  1  22/91 (24.18%)  13/90 (14.44%)  13/90 (14.44%) 
Hyperglycaemia  1  4/91 (4.40%)  5/90 (5.56%)  4/90 (4.44%) 
Hyponatraemia  1  2/91 (2.20%)  4/90 (4.44%)  7/90 (7.78%) 
Hypomagnesaemia  1  5/91 (5.49%)  2/90 (2.22%)  5/90 (5.56%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  12/91 (13.19%)  22/90 (24.44%)  20/90 (22.22%) 
Arthralgia  1  12/91 (13.19%)  18/90 (20.00%)  12/90 (13.33%) 
Pain in extremity  1  13/91 (14.29%)  15/90 (16.67%)  8/90 (8.89%) 
Musculoskeletal pain  1  5/91 (5.49%)  13/90 (14.44%)  9/90 (10.00%) 
Muscle spasms  1  4/91 (4.40%)  6/90 (6.67%)  8/90 (8.89%) 
Myalgia  1  8/91 (8.79%)  4/90 (4.44%)  5/90 (5.56%) 
Muscular weakness  1  4/91 (4.40%)  5/90 (5.56%)  5/90 (5.56%) 
Pain in jaw  1  2/91 (2.20%)  5/90 (5.56%)  7/90 (7.78%) 
Bone pain  1  5/91 (5.49%)  4/90 (4.44%)  4/90 (4.44%) 
Musculoskeletal chest pain  1  2/91 (2.20%)  5/90 (5.56%)  4/90 (4.44%) 
Neck pain  1  3/91 (3.30%)  7/90 (7.78%)  1/90 (1.11%) 
Nervous system disorders       
Neuropathy peripheral  1  33/91 (36.26%)  32/90 (35.56%)  32/90 (35.56%) 
Peripheral sensory neuropathy  1  27/91 (29.67%)  30/90 (33.33%)  36/90 (40.00%) 
Dysgeusia  1  27/91 (29.67%)  22/90 (24.44%)  23/90 (25.56%) 
Headache  1  26/91 (28.57%)  29/90 (32.22%)  17/90 (18.89%) 
Dizziness  1  18/91 (19.78%)  22/90 (24.44%)  17/90 (18.89%) 
Paraesthesia  1  9/91 (9.89%)  12/90 (13.33%)  14/90 (15.56%) 
Hypoaesthesia  1  4/91 (4.40%)  5/90 (5.56%)  4/90 (4.44%) 
Psychiatric disorders       
Insomnia  1  19/91 (20.88%)  23/90 (25.56%)  27/90 (30.00%) 
Anxiety  1  13/91 (14.29%)  12/90 (13.33%)  8/90 (8.89%) 
Depression  1  9/91 (9.89%)  12/90 (13.33%)  11/90 (12.22%) 
Renal and urinary disorders       
Proteinuria  1  15/91 (16.48%)  15/90 (16.67%)  15/90 (16.67%) 
Dysuria  1  3/91 (3.30%)  4/90 (4.44%)  6/90 (6.67%) 
Respiratory, thoracic and mediastinal disorders       
Epistaxis  1  32/91 (35.16%)  30/90 (33.33%)  22/90 (24.44%) 
Cough  1  15/91 (16.48%)  30/90 (33.33%)  17/90 (18.89%) 
Rhinorrhoea  1  12/91 (13.19%)  13/90 (14.44%)  8/90 (8.89%) 
Oropharyngeal pain  1  7/91 (7.69%)  17/90 (18.89%)  7/90 (7.78%) 
Dysphonia  1  7/91 (7.69%)  3/90 (3.33%)  10/90 (11.11%) 
Nasal congestion  1  7/91 (7.69%)  4/90 (4.44%)  5/90 (5.56%) 
Hiccups  1  6/91 (6.59%)  5/90 (5.56%)  4/90 (4.44%) 
Pulmonary embolism  1  6/91 (6.59%)  2/90 (2.22%)  2/90 (2.22%) 
Dyspnoea  1  14/91 (15.38%)  15/90 (16.67%)  7/90 (7.78%) 
Skin and subcutaneous tissue disorders       
Palmar-plantar erythrodysaesthesia syndrome  1  22/91 (24.18%)  28/90 (31.11%)  23/90 (25.56%) 
Alopecia  1  24/91 (26.37%)  23/90 (25.56%)  14/90 (15.56%) 
Rash  1  9/91 (9.89%)  17/90 (18.89%)  9/90 (10.00%) 
Dry skin  1  7/91 (7.69%)  11/90 (12.22%)  12/90 (13.33%) 
Pruritus  1  6/91 (6.59%)  4/90 (4.44%)  9/90 (10.00%) 
Hyperhidrosis  1  7/91 (7.69%)  4/90 (4.44%)  1/90 (1.11%) 
Skin hyperpigmentation  1  7/91 (7.69%)  6/90 (6.67%)  4/90 (4.44%) 
Skin discolouration  1  3/91 (3.30%)  2/90 (2.22%)  5/90 (5.56%) 
Rash maculo-papular  1  2/91 (2.20%)  6/90 (6.67%)  1/90 (1.11%) 
Nail discolouration  1  0/91 (0.00%)  5/90 (5.56%)  1/90 (1.11%) 
Surgical and medical procedures       
Sinus operation  1  2/91 (2.20%)  5/90 (5.56%)  1/90 (1.11%) 
Vascular disorders       
Hypertension  1  35/91 (38.46%)  36/90 (40.00%)  24/90 (26.67%) 
Hot flush  1  10/91 (10.99%)  6/90 (6.67%)  3/90 (3.33%) 
Hypotension  1  7/91 (7.69%)  2/90 (2.22%)  10/90 (11.11%) 
Deep vein thrombosis  1  4/91 (4.40%)  7/90 (7.78%)  6/90 (6.67%) 
Embolism  1  1/91 (1.10%)  5/90 (5.56%)  0/90 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
This trial was terminated on 12 November 2015, because the primary objective was not met.
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: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01765582     History of Changes
Other Study ID Numbers: ML28442
First Submitted: January 9, 2013
First Posted: January 10, 2013
Results First Submitted: June 2, 2017
Results First Posted: September 18, 2017
Last Update Posted: September 18, 2017