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A Study of Biomarker-Driven Therapy in Metastatic Colorectal Cancer (mCRC) (MODUL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02291289
Recruitment Status : Active, not recruiting
First Posted : November 14, 2014
Results First Posted : July 24, 2020
Last Update Posted : July 24, 2020
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 Cancer
Interventions Drug: Cetuximab
Drug: FOLFOX induction regimen
Drug: Fluoropyrimidine (5-FU/LV or capecitabine)
Drug: Atezolizumab
Drug: Vemurafenib
Drug: Bevacizumab
Drug: Trastuzumab
Drug: Pertuzumab
Drug: Cobimetinib
Drug: 5-FU/LV
Enrollment 609
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Cohort 1: Induction Phase (IP) Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2 (IP) Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (IP) Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (IP) Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description Included participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. Included participants with BRAFwt. All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. Included participants with human epidermal growth factor receptor 2 positive (HER2+). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. Included participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Period Title: Induction Treatment
Started 60 0 0 445 0 0 5 0 0 99 0 0
Completed [1] 58 0 0 436 0 0 5 0 0 98 0 0
Not Completed 2 0 0 9 0 0 0 0 0 1 0 0
Reason Not Completed
Not Dosed             2             0             0             9             0             0             0             0             0             1             0             0
[1]
Completed = dosed
Period Title: Maintenance Treatment Phase
Started 0 [1] 40 [1] 20 [1] 0 [1] 297 [1] 148 [1] 0 [1] 3 [1] 2 [1] 0 [1] 65 [1] 34 [1]
Dosed 0 40 18 0 293 143 0 3 2 0 64 34
Completed 0 16 4 0 45 19 0 1 0 0 34 18
Not Completed 0 24 16 0 252 129 0 2 2 0 31 16
Reason Not Completed
Withdrawal by Subject             0             0             0             0             13             11             0             0             0             0             2             3
Protocol Violation             0             1             0             0             2             1             0             0             0             0             0             0
Death             0             23             13             0             185             100             0             1             1             0             26             11
Adverse Event             0             0             0             0             1             0             0             0             0             0             0             0
Lost to Follow-up             0             0             0             0             12             3             0             1             0             0             2             1
Other             0             0             1             0             29             8             0             0             1             0             0             0
Physician Decision             0             0             0             0             2             0             0             0             0             0             0             1
Multiple Reasons             0             0             0             0             4             1             0             0             0             0             0             0
No Treatment Received             0             0             2             0             4             5             0             0             0             0             1             0
[1]
Participants from IP Cohorts were randomized to the MP Cohorts based on bio-marker assessments.
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
Hide Arm/Group Description Included participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) Included participants with BRAFwt Included participants with human epidermal growth factor receptor 2 positive (HER2+) Included participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) Total of all reporting groups
Overall Number of Baseline Participants 60 445 5 99 609
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 60 participants 445 participants 5 participants 99 participants 609 participants
59.2  (11.0) 60.6  (12.3) 49.6  (7.4) 59.5  (10.2) 60.5  (11.9)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 445 participants 5 participants 99 participants 609 participants
In utero
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Preterm newborn infants (gestational age < 37 wks)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Newborns (0-27 days)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Infants and toddlers (28 days-23 months)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Children (2-11 years)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Adolescents (12-17 years)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Adults (18-64 years)
39
  65.0%
254
  57.1%
5
 100.0%
66
  66.7%
364
  59.8%
From 65-84 years
21
  35.0%
189
  42.5%
0
   0.0%
33
  33.3%
243
  39.9%
85 years and over
0
   0.0%
2
   0.4%
0
   0.0%
0
   0.0%
2
   0.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 445 participants 5 participants 99 participants 609 participants
Female
34
  56.7%
174
  39.1%
3
  60.0%
41
  41.4%
252
  41.4%
Male
26
  43.3%
271
  60.9%
2
  40.0%
58
  58.6%
357
  58.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 60 participants 445 participants 5 participants 99 participants 609 participants
American Indian/Native Alaskan
1
   1.7%
7
   1.6%
0
   0.0%
2
   2.0%
10
   1.6%
Asian
3
   5.0%
12
   2.7%
0
   0.0%
12
  12.1%
27
   4.4%
Black or African American
0
   0.0%
6
   1.3%
0
   0.0%
1
   1.0%
7
   1.1%
Native Hawaiian or other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
50
  83.3%
375
  84.3%
5
 100.0%
81
  81.8%
511
  83.9%
Multiple
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown
6
  10.0%
45
  10.1%
0
   0.0%
3
   3.0%
54
   8.9%
1.Primary Outcome
Title Progression-Free Survival (PFS)
Hide Description PFS is defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
Time Frame From randomization until disease progression or death from any cause, up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description:
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Overall Number of Participants Analyzed 40 20 297 148 3 2 65 34
Median (95% Confidence Interval)
Unit of Measure: months
9.99
(7.72 to 12.55)
11.60
(3.58 to 15.67)
7.13
(6.14 to 8.41)
7.36
(5.82 to 8.94)
4.44
(3.55 to 14.69)
4.04
(4.04 to 5.39)
3.75
(3.42 to 3.91)
7.79
(3.98 to 9.46)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib, Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.872
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.50 to 1.82
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab, Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.666
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.77 to 1.18
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohort 4 (MP): Cobimetinib,Atezolizumab, Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.128
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.44
Confidence Interval (2-Sided) 95%
0.90 to 2.29
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival
Hide Description [Not Specified]
Time Frame From randomization until death from any cause, up to 5 years
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Percentage of Participants With Adverse Events
Hide Description [Not Specified]
Time Frame From baseline until end of study (up to 5 years)
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Overall Response
Hide Description Calculated as the number of participants with a best overall response of CR or PR according to RECIST 1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR= CR + PR.
Time Frame From randomization until disease progression, up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control(MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description:
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Overall Number of Participants Analyzed 40 20 297 148 3 2 65 34
Measure Type: Count of Participants
Unit of Measure: Participants
20
  50.0%
5
  25.0%
49
  16.5%
22
  14.9%
1
  33.3%
0
   0.0%
7
  10.8%
8
  23.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib, Cohort 1 Control(MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.064
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab, Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.658
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohort 4 (MP): Cobimetinib,Atezolizumab, Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.093
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
5.Secondary Outcome
Title Disease Control Rate (DCR)
Hide Description DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
Time Frame From randomization until disease progression, up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control(MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2(MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description:
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Overall Number of Participants Analyzed 40 20 297 148 3 2 65 34
Measure Type: Count of Participants
Unit of Measure: Participants
36
  90.0%
15
  75.0%
227
  76.4%
111
  75.0%
1
  33.3%
0
   0.0%
44
  67.7%
26
  76.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib, Cohort 1 Control(MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.125
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort 2(MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab, Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.739
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohort 4 (MP): Cobimetinib,Atezolizumab, Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.362
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
6.Secondary Outcome
Title Time to Treatment Response
Hide Description Calculated as the time from randomization to the first Occurrence of a documented Objective Response (CR or PR) determined according to RECIST 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame From randomization until disease progression or death from any cause, up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control(MP):5-FU/LV or Capecitabin, Bevacizumab Cohort 2(MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description:
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Overall Number of Participants Analyzed 40 20 297 148 3 2 65 34
Median (Full Range)
Unit of Measure: months
3.943
(1.18 to 29.70)
5.552
(1.38 to 8.02)
5.224
(1.22 to 26.74)
4.616
(1.25 to 19.91)
5.490
(5.490 to 5.490)
0
(0 to 0)
3.745
(1.77 to 14.92)
2.530
(1.64 to 11.83)
7.Secondary Outcome
Title Duration of Response
Hide Description Defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time Frame From first objective response until disease progression or death from any cause, up to 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control(MP):5-FU/LV or Capecitabin, Bevacizumab Cohort 2(MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description:
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Overall Number of Participants Analyzed 40 20 297 148 3 2 65 34
Median (95% Confidence Interval)
Unit of Measure: months
11.50
(7.66 to 21.49)
8.74
(5.36 to 19.02)
9.30
(5.55 to 11.30)
7.59
(6.93 to 13.90)
9.205
(9.205 to 9.205)
0
(0 to 0)
7.11 [1] 
(1.48 to NA)
6.06
(2.20 to 7.33)
[1]
Upper value of the 95% CI cannot be calculated because it is above the maximum value observed.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib, Cohort 1 Control(MP):5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.421
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort 2(MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab, Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.495
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohort 4 (MP): Cobimetinib,Atezolizumab, Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.357
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
8.Secondary Outcome
Title Percentage of Participants With Improvement and/or Stayed the Same on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score
Hide Description [Not Specified]
Time Frame From baseline until end of study (up to 5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control(MP):5-FU/LV or Capecitabin, Bevacizumab Cohort 2(MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description:
Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
Overall Number of Participants Analyzed 40 20 297 148 3 2 65 34
Measure Type: Number
Unit of Measure: percentage of participants
Improved 10.0 5.0 10.4 5.4 0 0 7.7 5.9
Improved or stayed the same 75.0 85.0 76.7 82.5 100 100 63.1 79.4
Time Frame From baseline until end of study (up to 5 years)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cohort 1: Induction Phase (IP) Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2 (IP) Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (IP) Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (IP) Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Hide Arm/Group Description Included participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. Included participants with BRAFwt. All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. Included participants with human epidermal growth factor receptor 2 positive (HER2+). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle. Included participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut). All study participants received either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab during Induction Treatment. Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle. Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
All-Cause Mortality
Cohort 1: Induction Phase (IP) Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2 (IP) Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (IP) Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (IP) Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   36/58 (62.07%)      23/40 (57.50%)      13/18 (72.22%)      292/436 (66.97%)      185/293 (63.14%)      100/143 (69.93%)      2/5 (40.00%)      1/3 (33.33%)      1/2 (50.00%)      38/98 (38.78%)      26/64 (40.63%)      11/34 (32.35%)    
Hide Serious Adverse Events
Cohort 1: Induction Phase (IP) Cohort 1 (Maintenance Phase[MP]):5-FU/LV,Cetuximab,Vemurafenib Cohort 1 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 2 (IP) Cohort 2 (MP):5-FU/LV or Capecitabine,Bevacizumab,Atezolizumab Cohort 2 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 3 (IP) Cohort 3 (MP): Capecitabine,Trastuzumab,Pertuzumab Cohort 3 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab Cohort 4 (IP) Cohort 4 (MP): Cobimetinib,Atezolizumab Cohort 4 Control (MP): 5-FU/LV or Capecitabin, Bevacizumab
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   9/58 (15.52%)      13/40 (32.50%)      8/18 (44.44%)      16/436 (3.67%)      90/293 (30.72%)      30/143 (20.98%)      0/5 (0.00%)      0/3 (0.00%)      0/2 (0.00%)      6/98 (6.12%)      25/64 (39.06%)      3/34 (8.82%)    
Blood and lymphatic system disorders                         
Anaemia  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/98 (1.02%)  1 0/64 (0.00%)  0 0/34 (0.00%)  0
Febrile neutropenia  1  0/58 (0.00%)  0 1/40 (2.50%)  1 1/18 (5.56%)  1 0/436 (0.00%)  0 5/293 (1.71%)  5 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Neutropenia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 4/293 (1.37%)  5 2/143 (1.40%)  4 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Cardiac disorders                         
Atrial fibrillation  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Cardiogenic shock  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/98 (1.02%)  1 0/64 (0.00%)  0 0/34 (0.00%)  0
Coronary artery disease  1  1/58 (1.72%)  1 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Myocardial infarction  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Myocardial ischaemia  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 1/436 (0.23%)  1 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Pericardial effusion  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Restrictive cardiomyopathy  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Supraventricular tachycardia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Ear and labyrinth disorders                         
Vertigo  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Endocrine disorders                         
Hypothyroidism  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Eye disorders                         
Chorioretinopathy  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/98 (1.02%)  1 0/64 (0.00%)  0 0/34 (0.00%)  0
Gastrointestinal disorders                         
Abdominal pain  1  1/58 (1.72%)  1 0/40 (0.00%)  0 0/18 (0.00%)  0 2/436 (0.46%)  2 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 2/98 (2.04%)  2 0/64 (0.00%)  0 1/34 (2.94%)  1
Abdominal pain upper  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Colitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 3/293 (1.02%)  3 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 1/34 (2.94%)  1
Constipation  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 4/293 (1.37%)  6 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Diarrhoea  1  1/58 (1.72%)  1 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 7/293 (2.39%)  7 2/143 (1.40%)  2 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  2 0/34 (0.00%)  0
Faecaloma  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Gastrointestinal obstruction  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Gastrooesophageal reflux disease  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Ileus  1  0/58 (0.00%)  0 1/40 (2.50%)  1 1/18 (5.56%)  1 0/436 (0.00%)  0 4/293 (1.37%)  4 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Immune-mediated enterocolitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Intestinal obstruction  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 2/143 (1.40%)  2 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 3/64 (4.69%)  3 0/34 (0.00%)  0
Intestinal perforation  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Large intestinal obstruction  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  3 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Large intestinal stenosis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Large intestine perforation  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Lower gastrointestinal haemorrhage  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 2/293 (0.68%)  2 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Nausea  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 3/293 (1.02%)  3 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Oesophagitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 2/293 (0.68%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Proctalgia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Rectal haemorrhage  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Small intestinal obstruction  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Stomatitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Subileus  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 2/293 (0.68%)  3 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  2 0/34 (0.00%)  0
Vomiting  1  0/58 (0.00%)  0 1/40 (2.50%)  3 0/18 (0.00%)  0 0/436 (0.00%)  0 5/293 (1.71%)  5 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
General disorders                         
Asthenia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Chest pain  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 1/436 (0.23%)  1 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Fatigue  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Gait disturbance  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
General physical health deterioration  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hyperthermia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Implant site dehiscence  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Implant site thrombosis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Infusion site extravasation  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Pyrexia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 9/293 (3.07%)  9 2/143 (1.40%)  3 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 2/64 (3.13%)  2 0/34 (0.00%)  0
Hepatobiliary disorders                         
Cholestasis  1  2/58 (3.45%)  2 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hepatic failure  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hepatitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hepatocellular injury  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hepatorenal failure  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hepatotoxicity  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Immune system disorders                         
Anaphylactic reaction  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hypersensitivity  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Infections and infestations                         
Abdominal abscess  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Abdominal infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Abdominal wall abscess  1  1/58 (1.72%)  1 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Anal abscess  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Arthritis infective  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Bronchitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Device related infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Diverticulitis  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Erysipelas  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Gastroenteritis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 1/436 (0.23%)  1 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Gastroenteritis clostridial  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Gingivitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hepatic infection  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Labyrinthitis  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Large intestine infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Lower respiratory tract infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Lung infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Pneumonia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 3/293 (1.02%)  3 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Pyelonephritis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Rectal abscess  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Respiratory tract infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Sepsis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 3/293 (1.02%)  3 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Septic shock  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Staphylococcal infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Upper respiratory tract infection  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Urinary tract infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 3/293 (1.02%)  3 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 2/64 (3.13%)  2 0/34 (0.00%)  0
Urosepsis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Vascular device infection  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 1/293 (0.34%)  1 2/143 (1.40%)  2 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Injury, poisoning and procedural complications                         
Anastomotic ulcer  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Femur fracture  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Incisional hernia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Post procedural haemorrhage  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Pubis fracture  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Rib fracture  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Spinal fracture  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Stoma site haemorrhage  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Tendon rupture  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Tibia fracture  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Tracheal haemorrhage  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Investigations                         
Blood creatine phosphokinase increased  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 3/64 (4.69%)  3 0/34 (0.00%)  0
Blood lactate dehydrogenase increased  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Blood triglycerides increased  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Lipase increased  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Neutrophil count decreased  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 2/143 (1.40%)  3 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Metabolism and nutrition disorders                         
Dehydration  1  1/58 (1.72%)  1 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Diabetic ketoacidosis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hyperglycaemia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hypoglycaemia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hypokalaemia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 2/293 (0.68%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hyponatraemia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Musculoskeletal and connective tissue disorders                         
Arthralgia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 1/34 (2.94%)  1
Back pain  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 1/34 (2.94%)  1
Muscular weakness  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Osteonecrosis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                         
Cancer pain  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Second primary malignancy  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Tumour perforation  1  1/58 (1.72%)  1 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Nervous system disorders                         
Cerebrovascular accident  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 1/34 (2.94%)  1
Haemorrhage intracranial  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Hypoaesthesia  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Peripheral motor neuropathy  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Presyncope  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Syncope  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Psychiatric disorders                         
Disorientation  1  0/58 (0.00%)  0 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Renal and urinary disorders                         
Acute kidney injury  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 4/436 (0.92%)  4 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/98 (1.02%)  1 1/64 (1.56%)  1 0/34 (0.00%)  0
Nephrolithiasis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Renal failure  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                         
Chronic obstructive pulmonary disease  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Dyspnoea  1  1/58 (1.72%)  1 0/40 (0.00%)  0 1/18 (5.56%)  1 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Epistaxis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Interstitial lung disease  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Pneumonitis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 2/64 (3.13%)  2 0/34 (0.00%)  0
Pneumothorax  1  0/58 (0.00%)  0 1/40 (2.50%)  1 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Pulmonary embolism  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 3/293 (1.02%)  3 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Respiratory failure  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Skin and subcutaneous tissue disorders                         
Rash  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Rash maculo-papular  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 1/64 (1.56%)  1 0/34 (0.00%)  0
Urticaria  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 1/143 (0.70%)  1 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Surgical and medical procedures                         
Ureteral stent removal  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Vascular disorders                         
Arterial thrombosis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 1/293 (0.34%)  1 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Deep vein thrombosis  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 2/293 (0.68%)  2 0/143 (0.00%)  0 0/5 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/98 (0.00%)  0 0/64 (0.00%)  0 0/34 (0.00%)  0
Haemorrhage  1  0/58 (0.00%)  0 0/40 (0.00%)  0 0/18 (0.00%)  0 0/436 (0.00%)  0 0/293 (0.00%)  0 0/143 (0.00%)  0 0/5 (0.00%)  0