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Trial record 2 of 54 for:    colon cancer | ( Map: Mississippi, United States )

Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery For Stage III Colon Cancer

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: NCT00079274
Recruitment Status : Completed
First Posted : March 10, 2004
Results First Posted : February 9, 2015
Last Update Posted : December 18, 2018
Sponsor:
Collaborator:
Eastern Cooperative Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adenocarcinoma of the Colon
Stage III Colon Cancer
Interventions Drug: irinotecan hydrochloride
Drug: oxaliplatin
Drug: leucovorin calcium
Drug: fluorouracil
Biological: cetuximab
Drug: Locally Directed Therapy
Enrollment 3397
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm A (Combination Chemotherapy) Arm B (Combination Chemotherapy) Arm C (Combination Chemotherapy) Arm D (Combination Chemotherapy, Monoclonal Antibody) Arm E (Combination Chemotherapy, Monoclonal Antibody) Arm F (Combination Chemotherapy, Monoclonal Antibody) Arm G (Locally Directed Therapy)
Hide Arm/Group Description

Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

leucovorin calcium: Given IV

fluorouracil: Given I

cetuximab: Given IV

Patients received cetuximab as in arm D and chemotherapy as in arm C.

irinotecan hydrochloride: Given IV

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients determined to have mutated Kirsten rat sarcoma (KRAS) (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.

Locally Directed Therapy: Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.

Period Title: Overall Study
Started 1402 111 111 1350 45 46 332
Completed 1081 84 84 906 30 26 332
Not Completed 321 27 27 444 15 20 0
Reason Not Completed
Withdrawal by Subject             111             10             12             163             7             8             0
Adverse Event             130             8             8             184             7             8             0
Recurrence             21             0             1             15             0             2             0
Alternate Treatment             6             1             0             3             0             0             0
Other Medical Problems             6             1             0             7             0             0             0
Death             4             0             1             15             0             0             0
Cytogenetic resistance             0             0             0             2             0             0             0
Not Specified             43             7             5             55             1             2             0
Arm/Group Title Arm A (Combination Chemotherapy) Arm B (Combination Chemotherapy) Arm C (Combination Chemotherapy) Arm D (Combination Chemotherapy, Monoclonal Antibody) Arm E (Combination Chemotherapy, Monoclonal Antibody) Arm F (Combination Chemotherapy, Monoclonal Antibody) Arm G (Locally Directed Therapy) Total
Hide Arm/Group Description

Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients received cetuximab as in arm D and chemotherapy as in arm C.

irinotecan hydrochloride: Given IV

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.

Locally Directed Therapy: Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.

Total of all reporting groups
Overall Number of Baseline Participants 1402 111 111 1350 45 46 332 3397
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
58
(19 to 85)
57
(25 to 82)
60
(24 to 82)
58
(22 to 86)
59
(30 to 82)
60.5
(30 to 81)
56
(22 to 84)
58
(19 to 86)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
Female
662
  47.2%
53
  47.7%
50
  45.0%
647
  47.9%
20
  44.4%
21
  45.7%
160
  48.2%
1613
  47.5%
Male
740
  52.8%
58
  52.3%
61
  55.0%
703
  52.1%
25
  55.6%
25
  54.3%
172
  51.8%
1784
  52.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
Hispanic or Latino
64
   4.6%
5
   4.5%
3
   2.7%
62
   4.6%
4
   8.9%
2
   4.3%
18
   5.4%
158
   4.7%
Not Hispanic or Latino
1107
  79.0%
103
  92.8%
103
  92.8%
1060
  78.5%
38
  84.4%
41
  89.1%
225
  67.8%
2677
  78.8%
Unknown or Not Reported
231
  16.5%
3
   2.7%
5
   4.5%
228
  16.9%
3
   6.7%
3
   6.5%
89
  26.8%
562
  16.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
American Indian or Alaska Native
6
   0.4%
1
   0.9%
1
   0.9%
7
   0.5%
0
   0.0%
0
   0.0%
1
   0.3%
16
   0.5%
Asian
66
   4.7%
4
   3.6%
2
   1.8%
62
   4.6%
3
   6.7%
0
   0.0%
12
   3.6%
149
   4.4%
Native Hawaiian or Other Pacific Islander
8
   0.6%
0
   0.0%
1
   0.9%
7
   0.5%
0
   0.0%
0
   0.0%
0
   0.0%
16
   0.5%
Black or African American
94
   6.7%
6
   5.4%
7
   6.3%
96
   7.1%
5
  11.1%
2
   4.3%
29
   8.7%
239
   7.0%
White
1202
  85.7%
98
  88.3%
100
  90.1%
1154
  85.5%
37
  82.2%
43
  93.5%
275
  82.8%
2909
  85.6%
More than one race
3
   0.2%
2
   1.8%
0
   0.0%
3
   0.2%
0
   0.0%
0
   0.0%
1
   0.3%
9
   0.3%
Unknown or Not Reported
23
   1.6%
0
   0.0%
0
   0.0%
21
   1.6%
0
   0.0%
1
   2.2%
14
   4.2%
59
   1.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
United States 1258 109 109 1224 44 46 303 3093
Canada 138 2 2 124 1 0 28 295
Jamaica 1 0 0 0 0 0 0 1
Puerto Rico 5 0 0 2 0 0 1 8
Positive Nodes   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
1-3 816 71 70 790 29 28 203 2007
4+ 586 40 41 560 16 18 129 1390
[1]
Measure Description: Number of positive nodes
Tumor Stage   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
T1 or T2 198 18 14 213 5 5 56 509
T3 1046 78 93 983 35 39 214 2488
T4 158 15 4 153 4 2 62 398
Not Availabe 0 0 0 1 1 0 0 2
[1]
Measure Description:

T1: Tumor invades submucosa

T2: Tumor invades muscularis propria

T3: Tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissues

T4: (T4a+) Tumor perforates the visceral peritoneum without adherence to or invasion of other organs or structures or (T4b) Tumor is adherent to or directly invades other organs or structures

Histologic Grade   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
High 357 25 28 345 10 12 60 837
Low 1045 86 83 1005 35 34 272 2560
[1]
Measure Description: High=poorly differentiated or undifferentiated > Low=well or moderately differentiated
KRAS Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1402 participants 111 participants 111 participants 1350 participants 45 participants 46 participants 332 participants 3397 participants
Unknown 56 6 6 51 3 4 6 132
Mutant 391 33 43 345 15 13 326 1166
Wildtype 955 72 62 954 27 29 0 2099
1.Primary Outcome
Title Disease-free Survival (Arms A and D: Wild-type KRAS Patients)
Hide Description

The primary endpoint for this study was to compare the disease-free survival (DFS) in patients with stage III colon cancer who are KRAS wild-type randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint.

Disease-free survival is defined as the time from randomization until tumor recurrence or death, whichever is first. Estimated by the method of Kaplan and Meier.

Time Frame At 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed using intention to treat principles. All patients that were wild-type KRAS and received randomized treatment according to the Arm A or Arm D intervention schedule were evaluated for this endpoint. Any patient receiving irinotecan was not included in the evaluation of this endpoint.
Arm/Group Title Wild-type KRAS Arm A Wild-type KRAS Arm D
Hide Arm/Group Description:
Patients from Arm A (and a few patients from Arm C that did not receive irinotecan) that are wild-type KRAS and concurrently randomized with Arm D patients.
Patients from Arm D (and a few patients from Arm F that did not receive irinotecan) that are wild-type KRAS and concurrently randomized with Arm A patients.
Overall Number of Participants Analyzed 909 954
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
74.6
(71.1 to 78.3)
71.5
(67.8 to 75.4)
2.Secondary Outcome
Title Disease-free Survival (Arms A and D: Mutant KRAS Patients)
Hide Description

A secondary endpoint for this study was to investigate the disease-free survival (DFS) in patients with stage III colon cancer who are KRAS mutant (or KRAS-nonevaluable) and randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint.

Disease-free survival is defined as the time from randomization until tumor recurrence or death, whichever is first. Estimated by the method of Kaplan and Meier.

Time Frame At 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed using intention to treat principles. All patients that were KRAS mutant (or not evaluable for KRAS) and received randomized treatment according to the Arm A or Arm D intervention schedule were evaluated for this endpoint. Any patient receiving irinotecan was not included in the evaluation of this endpoint.
Arm/Group Title Mutant KRAS Arm A Mutant KRAS Arm D
Hide Arm/Group Description:
Patients from Arm A (and a few patients from Arm C that did not receive irinotecan) that are mutant KRAS and concurrently randomized with Arm D patients.
Patients from Arm D (and a few patients from Arm F that did not receive irinotecan) that are mutant KRAS and concurrently randomized with Arm A patients.
Overall Number of Participants Analyzed 374 343
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
67.1
(61.8 to 72.8)
65.0
(59.8 to 70.7)
3.Secondary Outcome
Title Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Wild-type KRAS Patients)
Hide Description Evidence of death from any cause within 3 years counted as events in the time to event- Kaplan Meier analysis of overall survival for patients with stage III colon cancer who are KRAS wild-type randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint. The 3-year event free rates (percentage) are reported below for Wild-type KRAS Patients.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed using intention to treat principles. All patients that were wild-type KRAS and received randomized treatment according to the Arm A or Arm D intervention schedule were evaluated for this endpoint. Any patient receiving irinotecan was not included in the evaluation of this endpoint.
Arm/Group Title Wild-type KRAS Arm A Wild-type KRAS Arm D
Hide Arm/Group Description:
Patients from Arm A (and a few patients from Arm C that did not receive irinotecan) that are wild-type KRAS and concurrently randomized with Arm D patients.
Patients from Arm D (and a few patients from Arm F that did not receive irinotecan) that are wild-type KRAS and concurrently randomized with Arm A patients.
Overall Number of Participants Analyzed 909 954
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
87.3
(84.3 to 90.3)
85.6
(82.7 to 88.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wild-type KRAS Arm A, Wild-type KRAS Arm D
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.15
Comments [Not Specified]
Method Regression, Cox
Comments HR and p-value reported from a multivariate Cox PH regression model, adjusted for number of nodes, histologic grade, and T stage.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.25
Confidence Interval (2-Sided) 95%
0.92 to 1.68
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Overall Survival as Measured by the 3-year Event-free Rate (Arms A and D: Mutant KRAS Patients)
Hide Description Evidence of death from any cause within 3 years counted as events in the time to event- Kaplan Meier analysis of overall survival for patients with stage III colon cancer who are KRAS mutant (or KRAS-nonevaluable) and randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). Participants treated according to Arms B, C, E, and F treatment schedules received treatment which included irinotecan hydrochloride and therefore were not analyzed for this endpoint. The 3-year event-free rates (percentage) are report below for mutant KRAS patients.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was performed using intention to treat principles. All patients that were KRAS mutant (or not evaluable for KRAS) and received randomized treatment according to the Arm A or Arm D intervention schedule were evaluated for this endpoint. Any patient receiving irinotecan was not included in the evaluation of this endpoint.
Arm/Group Title Mutant KRAS Arm A Mutant KRAS Arm D
Hide Arm/Group Description:
Patients from Arm A (and a few patients from Arm C that did not receive irinotecan) that are mutant KRAS and concurrently randomized with Arm D patients.
Patients from Arm D (and a few patients from Arm F that did not receive irinotecan) that are mutant KRAS and concurrently randomized with Arm A patients.
Overall Number of Participants Analyzed 374 343
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
87.9
(84.0 to 91.9)
82.7
(78.0 to 87.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mutant KRAS Arm A, Mutant KRAS Arm D
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.25
Comments [Not Specified]
Method Regression, Cox
Comments HR and p-value reported from a multivariate Cox PH regression model, adjusted for number of nodes, histologic grade, and T stage.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.27
Confidence Interval (2-Sided) 95%
0.85 to 1.92
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) (Arms A and D: Wild-type KRAS Patients)
Hide Description The maximum grade for each type of toxicity will be recorded for each patient with stage III colon cancer who are KRAS wild-type randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time Frame Assessed up to 8 years
Hide Outcome Measure Data
Hide Analysis Population Description
All patients that were wild-type KRAS and received randomized treatment according to the Arm A or Arm D intervention schedule and completed the adverse event form at least once were evaluated for this endpoint.
Arm/Group Title Wild-type KRAS Arm A Wild-type KRAS Arm D
Hide Arm/Group Description:
Patients from Arm A (and a few patients from Arm C that did not receive irinotecan) that are wild-type KRAS and concurrently randomized with Arm D patients.
Patients from Arm D (and a few patients from Arm F that did not receive irinotecan) that are wild-type KRAS and concurrently randomized with Arm A patients.
Overall Number of Participants Analyzed 894 931
Measure Type: Number
Unit of Measure: percentage of patients
51.1 73.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wild-type KRAS Arm A, Wild-type KRAS Arm D
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments two-sided chi-squared test
6.Secondary Outcome
Title Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) (Arms A and D: Mutant KRAS Patients)
Hide Description The maximum grade for each type of toxicity will be recorded for each patient with stage III colon cancer who are KRAS mutant (or KRAS-nonevaluable) and randomized to one of two treatment regimens: 1) oxaliplatin, leucovorin calcium, and fluorouracil (Arm A) or 2) oxaliplatin, leucovorin calcium, fluorouracil and cetuximab (Arm D). The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time Frame Assessed up to 8 years
Hide Outcome Measure Data
Hide Analysis Population Description
All patients that were mutant KRAS and received randomized treatment according to the Arm A or Arm D intervention schedule and completed the adverse event form at least once were evaluated for this endpoint.
Arm/Group Title Mutant KRAS Arm A Mutant KRAS Arm D
Hide Arm/Group Description:
Patients from Arm A (and a few patients from Arm C that did not receive irinotecan) that are mutant KRAS and concurrently randomized with Arm D patients.
Patients from Arm D (and a few patients from Arm F that did not receive irinotecan) that are mutant KRAS and concurrently randomized with Arm A patients.
Overall Number of Participants Analyzed 367 342
Measure Type: Number
Unit of Measure: percentage of patients
55.6 72.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mutant KRAS Arm A, Mutant KRAS Arm D
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Chi-squared
Comments Two-sided chi-squared test
Time Frame 6 months or during treatment
Adverse Event Reporting Description All patients that received protocol treatment and completed at least one adverse event assessment are included in this analysis. Adverse event data was not collected for Arm G patients.
 
Arm/Group Title Arm A (Combination Chemotherapy) Arm B (Combination Chemotherapy) Arm C (Combination Chemotherapy) Arm D (Combination Chemotherapy, Monoclonal Antibody) Arm E (Combination Chemotherapy, Monoclonal Antibody) Arm F (Combination Chemotherapy, Monoclonal Antibody) Arm G (Locally Directed Therapy)
Hide Arm/Group Description

Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients receive irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients receive the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

Patients receive cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients receive cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

irinotecan hydrochloride: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients receive cetuximab as in arm D and chemotherapy as in arm C.

irinotecan hydrochloride: Given IV

oxaliplatin: Given IV

leucovorin calcium: Given IV

fluorouracil: Given IV

cetuximab: Given IV

Patients determined to have mutated KRAS (or KRAS not evaluable) will be assigned to an event monitoring arm in which adjuvant therapy will be determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification will be the responsibility of the treating oncologists.

Locally Directed Therapy: Patients determined to have mutated KRAS (or KRAS not evaluable) will be assigned to an event monitoring arm in which adjuvant therapy will be determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification will be the responsibility of the treating oncologists.

All-Cause Mortality
Arm A (Combination Chemotherapy) Arm B (Combination Chemotherapy) Arm C (Combination Chemotherapy) Arm D (Combination Chemotherapy, Monoclonal Antibody) Arm E (Combination Chemotherapy, Monoclonal Antibody) Arm F (Combination Chemotherapy, Monoclonal Antibody) Arm G (Locally Directed Therapy)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Arm A (Combination Chemotherapy) Arm B (Combination Chemotherapy) Arm C (Combination Chemotherapy) Arm D (Combination Chemotherapy, Monoclonal Antibody) Arm E (Combination Chemotherapy, Monoclonal Antibody) Arm F (Combination Chemotherapy, Monoclonal Antibody) Arm G (Locally Directed Therapy)
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   93/1378 (6.75%)      9/108 (8.33%)      11/108 (10.19%)      150/1326 (11.31%)      4/42 (9.52%)      5/44 (11.36%)      0/0    
Blood and lymphatic system disorders               
Febrile neutropenia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hemoglobin decreased  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cardiac disorders               
Asystole  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Atrial fibrillation  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  4 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Cardiac disorder  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cardiac pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 1/42 (2.38%)  1 1/44 (2.27%)  1 0/0  0
Cardiopulmonary arrest  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Left ventricular failure  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Myocardial ischemia  1  6/1378 (0.44%)  7 0/108 (0.00%)  0 1/108 (0.93%)  1 9/1326 (0.68%)  9 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Premature ventricular contractions  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Sinus tachycardia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Supraventricular tachycardia  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ventricular tachycardia  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ear and labyrinth disorders               
Tinnitus  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastrointestinal disorders               
Abdominal distension  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Abdominal pain  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 1/108 (0.93%)  1 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colitis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colonic fistula  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colonic obstruction  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colonic perforation  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colonic stenosis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Diarrhea  1  15/1378 (1.09%)  15 0/108 (0.00%)  0 1/108 (0.93%)  1 20/1326 (1.51%)  20 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ear, nose and throat examination abnormal  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Endoscopy small intestine abnormal  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Enteritis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Esophageal hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Esophageal ulcer  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastritis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ileus  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Mucositis oral  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Nausea  1  5/1378 (0.36%)  5 1/108 (0.93%)  1 1/108 (0.93%)  1 5/1326 (0.38%)  5 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pancreatitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Rectal hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Vomiting  1  3/1378 (0.22%)  3 1/108 (0.93%)  1 1/108 (0.93%)  1 5/1326 (0.38%)  5 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
General disorders               
Chest pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Death NOS  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Fatigue  1  3/1378 (0.22%)  3 1/108 (0.93%)  1 1/108 (0.93%)  1 4/1326 (0.30%)  4 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Sudden death  1  0/1378 (0.00%)  0 1/108 (0.93%)  1 1/108 (0.93%)  1 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hepatobiliary disorders               
Cholecystitis  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gallbladder pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hepatobiliary disease  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Immune system disorders               
Hypersensitivity  1  6/1378 (0.44%)  6 0/108 (0.00%)  0 0/108 (0.00%)  0 17/1326 (1.28%)  17 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Infections and infestations               
Abdominal infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Bladder infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Catheter related infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colitis, infectious (e.g., Clostridium difficile)  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Infectious colitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Infectious meningitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pneumonia  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Sepsis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 7/1326 (0.53%)  7 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Skin infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Urinary tract infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Wound infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Injury, poisoning and procedural complications               
Fracture  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Postoperative hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Investigations               
Activated partial thromboplastin time prolonged  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Alanine aminotransferase increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Amylase increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 1/108 (0.93%)  1 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Aspartate aminotransferase increased  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Blood bilirubin increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cardiac troponin I increased  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 2/42 (4.76%)  2 0/44 (0.00%)  0 0/0  0
Cardiac troponin T increased  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Creatine phosphokinase increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Creatinine increased  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
INR increased  1  4/1378 (0.29%)  5 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Lipase increased  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 1/108 (0.93%)  1 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Neutrophil count decreased  1  13/1378 (0.94%)  15 1/108 (0.93%)  1 1/108 (0.93%)  1 8/1326 (0.60%)  8 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Platelet count decreased  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Weight loss  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Metabolism and nutrition disorders               
Anorexia  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  5 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Blood glucose increased  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 1/108 (0.93%)  1 5/1326 (0.38%)  5 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Dehydration  1  7/1378 (0.51%)  7 1/108 (0.93%)  1 2/108 (1.85%)  2 10/1326 (0.75%)  10 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Glucose intolerance  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum calcium decreased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum glucose decreased  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum magnesium decreased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 6/1326 (0.45%)  6 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum phosphate decreased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum potassium decreased  1  10/1378 (0.73%)  10 0/108 (0.00%)  0 0/108 (0.00%)  0 20/1326 (1.51%)  20 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum sodium decreased  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Musculoskeletal and connective tissue disorders               
Chest wall pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Muscle weakness  1  0/1378 (0.00%)  0 1/108 (0.93%)  1 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Musculoskeletal disorder  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Myalgia  1  0/1378 (0.00%)  0 1/108 (0.93%)  1 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Myositis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Neck pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pain in extremity  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Nervous system disorders               
Ataxia  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Depressed level of consciousness  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Dizziness  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Encephalopathy  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Headache  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Intracranial hemorrhage  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  4 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ischemia cerebrovascular  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 1/108 (0.93%)  1 3/1326 (0.23%)  3 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Peripheral motor neuropathy  1  1/1378 (0.07%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Peripheral sensory neuropathy  1  1/1378 (0.07%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Seizure  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Speech disorder  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Syncope  1  6/1378 (0.44%)  6 0/108 (0.00%)  0 2/108 (1.85%)  2 5/1326 (0.38%)  5 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Psychiatric disorders               
Confusion  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Depression  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 1/108 (0.93%)  1 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Renal and urinary disorders               
Bladder hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ureteric obstruction  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Respiratory, thoracic and mediastinal disorders               
Bronchospasm  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cough  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Dyspnea  1  2/1378 (0.15%)  2 1/108 (0.93%)  1 2/108 (1.85%)  2 6/1326 (0.45%)  6 2/42 (4.76%)  2 2/44 (4.55%)  2 0/0  0
Hypoxia  1  2/1378 (0.15%)  2 1/108 (0.93%)  1 0/108 (0.00%)  0 3/1326 (0.23%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Laryngeal edema  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pleural effusion  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pneumonitis  1  2/1378 (0.15%)  2 1/108 (0.93%)  1 0/108 (0.00%)  0 5/1326 (0.38%)  5 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Pneumothorax  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pulmonary fibrosis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Respiratory disorder  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Skin and subcutaneous tissue disorders               
Erythema multiforme  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Masculinization  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Rash acneiform  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Rash desquamating  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Vascular disorders               
Hypertension  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hypotension  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 5/1326 (0.38%)  5 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Thrombosis  1  5/1378 (0.36%)  5 2/108 (1.85%)  2 0/108 (0.00%)  0 9/1326 (0.68%)  9 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 6
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm A (Combination Chemotherapy) Arm B (Combination Chemotherapy) Arm C (Combination Chemotherapy) Arm D (Combination Chemotherapy, Monoclonal Antibody) Arm E (Combination Chemotherapy, Monoclonal Antibody) Arm F (Combination Chemotherapy, Monoclonal Antibody) Arm G (Locally Directed Therapy)
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   688/1378 (49.93%)      53/108 (49.07%)      60/108 (55.56%)      928/1326 (69.98%)      26/42 (61.90%)      33/44 (75.00%)      0/0    
Blood and lymphatic system disorders               
Febrile neutropenia  1  12/1378 (0.87%)  12 2/108 (1.85%)  3 3/108 (2.78%)  3 30/1326 (2.26%)  33 1/42 (2.38%)  1 1/44 (2.27%)  1 0/0  0
Hemoglobin decreased  1  6/1378 (0.44%)  9 0/108 (0.00%)  0 0/108 (0.00%)  0 8/1326 (0.60%)  11 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Thrombotic microangiopathy  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 1/108 (0.93%)  1 3/1326 (0.23%)  3 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Cardiac disorders               
Arrhythmia  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Arrhythmia supraventricular  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Asystole  1  0/1378 (0.00%)  0 1/108 (0.93%)  1 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Atrial fibrillation  1  1/1378 (0.07%)  2 1/108 (0.93%)  1 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Atrial flutter  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Cardiac disorder  1  2/1378 (0.15%)  4 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cardiac pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Conduction disorder  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Myocardial ischemia  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  4 2/42 (4.76%)  2 0/44 (0.00%)  0 0/0  0
Premature ventricular contractions  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Sinus tachycardia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Supraventricular extrasystoles  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Supraventricular tachycardia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ventricular arrhythmia  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ear and labyrinth disorders               
Ear pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Tinnitus  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Eye disorders               
Cataract  1  1/1378 (0.07%)  8 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Conjunctivitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Eyelid function disorder  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Retinal detachment  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Watering eyes  1  1/1378 (0.07%)  1 1/108 (0.93%)  1 1/108 (0.93%)  1 2/1326 (0.15%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastrointestinal disorders               
Abdominal distension  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Abdominal pain  1  31/1378 (2.25%)  32 1/108 (0.93%)  1 2/108 (1.85%)  2 28/1326 (2.11%)  35 1/42 (2.38%)  1 3/44 (6.82%)  5 0/0  0
Anal pain  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cecal obstruction  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Cheilitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colitis  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 1/108 (0.93%)  1 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colonic obstruction  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Colonic stenosis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Constipation  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 9/1326 (0.68%)  10 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Diarrhea  1  107/1378 (7.76%)  125 15/108 (13.89%)  28 13/108 (12.04%)  17 192/1326 (14.48%)  250 6/42 (14.29%)  7 7/44 (15.91%)  11 0/0  0
Dry mouth  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Dyspepsia  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  4 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Dysphagia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ear, nose and throat examination abnormal  1  18/1378 (1.31%)  20 2/108 (1.85%)  2 2/108 (1.85%)  2 63/1326 (4.75%)  77 3/42 (7.14%)  4 1/44 (2.27%)  1 0/0  0
Enteritis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Esophagitis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastric hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastric ulcer  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastritis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gastrointestinal disorder  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Gastrointestinal pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hemorrhoids  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ileal obstruction  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ileal perforation  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ileus  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  5 0/42 (0.00%)  0 1/44 (2.27%)  2 0/0  0
Intestinal necrosis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Large intestinal mucositis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Lip pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Lower gastrointestinal hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Mucositis oral  1  18/1378 (1.31%)  19 2/108 (1.85%)  2 2/108 (1.85%)  6 44/1326 (3.32%)  51 3/42 (7.14%)  3 2/44 (4.55%)  2 0/0  0
Nausea  1  35/1378 (2.54%)  41 9/108 (8.33%)  10 6/108 (5.56%)  6 56/1326 (4.22%)  66 0/42 (0.00%)  0 8/44 (18.18%)  10 0/0  0
Oral pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pancreatitis  1  0/1378 (0.00%)  0 1/108 (0.93%)  1 1/108 (0.93%)  1 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Proctitis  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Rectal pain  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Rectal perforation  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Small intestinal obstruction  1  5/1378 (0.36%)  6 0/108 (0.00%)  0 1/108 (0.93%)  1 3/1326 (0.23%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Vomiting  1  40/1378 (2.90%)  44 7/108 (6.48%)  10 5/108 (4.63%)  5 41/1326 (3.09%)  45 0/42 (0.00%)  0 4/44 (9.09%)  6 0/0  0
General disorders               
Chest pain  1  5/1378 (0.36%)  6 1/108 (0.93%)  1 0/108 (0.00%)  0 6/1326 (0.45%)  6 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Edema limbs  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Fatigue  1  53/1378 (3.85%)  80 2/108 (1.85%)  2 9/108 (8.33%)  11 77/1326 (5.81%)  122 1/42 (2.38%)  1 2/44 (4.55%)  2 0/0  0
Flu-like symptoms  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gait abnormal  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
General symptom  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Ill-defined disorder  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pain  1  4/1378 (0.29%)  5 0/108 (0.00%)  0 0/108 (0.00%)  0 5/1326 (0.38%)  6 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hepatobiliary disorders               
Gallbladder obstruction  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hepatic failure  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hepatobiliary disease  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Immune system disorders               
Cytokine release syndrome  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hypersensitivity  1  28/1378 (2.03%)  29 0/108 (0.00%)  0 2/108 (1.85%)  2 62/1326 (4.68%)  65 1/42 (2.38%)  2 1/44 (2.27%)  1 0/0  0
Infections and infestations               
Abdominal infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  3 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Bladder infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Bronchitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 1/108 (0.93%)  1 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Catheter related infection  1  5/1378 (0.36%)  5 0/108 (0.00%)  0 1/108 (0.93%)  2 13/1326 (0.98%)  14 1/42 (2.38%)  1 1/44 (2.27%)  1 0/0  0
Colitis, infectious (e.g., Clostridium difficile)  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Device related infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Ileal infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Infection  1  5/1378 (0.36%)  5 0/108 (0.00%)  0 0/108 (0.00%)  0 6/1326 (0.45%)  6 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Infectious colitis  1  8/1378 (0.58%)  10 0/108 (0.00%)  0 0/108 (0.00%)  0 5/1326 (0.38%)  5 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Joint infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Kidney infection  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Nail infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  5 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Otitis media  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pelvic infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pharyngitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Pneumonia  1  10/1378 (0.73%)  10 0/108 (0.00%)  0 0/108 (0.00%)  0 5/1326 (0.38%)  5 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Salivary gland infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Sepsis  1  4/1378 (0.29%)  4 0/108 (0.00%)  0 0/108 (0.00%)  0 6/1326 (0.45%)  6 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Sinusitis  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Skin infection  1  3/1378 (0.22%)  4 1/108 (0.93%)  1 0/108 (0.00%)  0 24/1326 (1.81%)  41 1/42 (2.38%)  1 1/44 (2.27%)  1 0/0  0
Soft tissue infection  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Upper aerodigestive tract infection  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Upper respiratory infection  1  3/1378 (0.22%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 5/1326 (0.38%)  6 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Urinary tract infection  1  4/1378 (0.29%)  4 0/108 (0.00%)  0 0/108 (0.00%)  0 8/1326 (0.60%)  8 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Wound infection  1  2/1378 (0.15%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Injury, poisoning and procedural complications               
Arterial injury - Extremity-lower  1  0/1378 (0.00%)  0 1/108 (0.93%)  1 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Fracture  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 1/108 (0.93%)  1 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Injury to superior vena cava  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Intestinal stoma site bleeding  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Postoperative hemorrhage  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Vascular access complication  1  22/1378 (1.60%)  33 3/108 (2.78%)  3 5/108 (4.63%)  8 18/1326 (1.36%)  34 1/42 (2.38%)  1 2/44 (4.55%)  2 0/0  0
Investigations               
Activated partial thromboplastin time prolonged  1  1/1378 (0.07%)  2 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  4 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Alanine aminotransferase increased  1  16/1378 (1.16%)  21 1/108 (0.93%)  1 0/108 (0.00%)  0 14/1326 (1.06%)  18 1/42 (2.38%)  1 1/44 (2.27%)  1 0/0  0
Alkaline phosphatase increased  1  2/1378 (0.15%)  4 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Aspartate aminotransferase increased  1  10/1378 (0.73%)  10 0/108 (0.00%)  0 0/108 (0.00%)  0 11/1326 (0.83%)  12 1/42 (2.38%)  1 0/44 (0.00%)  0 0/0  0
Blood bilirubin increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Coagulopathy  1  3/1378 (0.22%)  7 0/108 (0.00%)  0 0/108 (0.00%)  0 3/1326 (0.23%)  10 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Creatinine increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Gamma-glutamyltransferase increased  1  2/1378 (0.15%)  5 0/108 (0.00%)  0 0/108 (0.00%)  0 2/1326 (0.15%)  4 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
INR increased  1  16/1378 (1.16%)  39 0/108 (0.00%)  0 1/108 (0.93%)  3 15/1326 (1.13%)  30 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Leukocyte count decreased  1  25/1378 (1.81%)  32 1/108 (0.93%)  1 0/108 (0.00%)  0 31/1326 (2.34%)  36 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Lipase increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Lymphocyte count decreased  1  5/1378 (0.36%)  6 0/108 (0.00%)  0 1/108 (0.93%)  1 8/1326 (0.60%)  14 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Neutrophil count decreased  1  131/1378 (9.51%)  148 14/108 (12.96%)  18 18/108 (16.67%)  20 154/1326 (11.61%)  175 3/42 (7.14%)  4 4/44 (9.09%)  4 0/0  0
Platelet count decreased  1  6/1378 (0.44%)  6 0/108 (0.00%)  0 0/108 (0.00%)  0 4/1326 (0.30%)  4 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum cholesterol increased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 0/1326 (0.00%)  0 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Weight gain  1  1/1378 (0.07%)  1 1/108 (0.93%)  4 0/108 (0.00%)  0 2/1326 (0.15%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Weight loss  1  2/1378 (0.15%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 9/1326 (0.68%)  18 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Metabolism and nutrition disorders               
Anorexia  1  9/1378 (0.65%)  9 1/108 (0.93%)  1 0/108 (0.00%)  0 28/1326 (2.11%)  35 1/42 (2.38%)  1 2/44 (4.55%)  3 0/0  0
Blood glucose increased  1  42/1378 (3.05%)  99 8/108 (7.41%)  37 6/108 (5.56%)  12 32/1326 (2.41%)  69 1/42 (2.38%)  2 1/44 (2.27%)  6 0/0  0
Dehydration  1  10/1378 (0.73%)  10 1/108 (0.93%)  1 3/108 (2.78%)  3 39/1326 (2.94%)  42 0/42 (0.00%)  0 1/44 (2.27%)  2 0/0  0
Hyperglycemia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hypokalemia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  1 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Hyponatremia  1  0/1378 (0.00%)  0 0/108 (0.00%)  0 0/108 (0.00%)  0 1/1326 (0.08%)  2 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum albumin decreased  1  2/1378 (0.15%)  3 0/108 (0.00%)  0 0/108 (0.00%)  0 8/1326 (0.60%)  11 0/42 (0.00%)  0 0/44 (0.00%)  0 0/0  0
Serum calcium decreased  1  6/1378 (0.44%)  6 0/108 (0.00%)  0 1/108 (0.93%)  1 9/1326 (0.68%)  9 0/42 (0.00%)  0 1/44 (2.27%)  1 0/0  0
Serum magnesium decreased  1  1/1378 (0.07%)  1 0/108 (0.00%)  0 0/108 (0.00%)  0 26/1326 (1.96%)  43 0/42 (0.00%)  0 2/44 (4.55%)  4 0/0  0
Serum magnesium increased  1  2/1378 (0.15%)