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

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ClinicalTrials.gov Identifier: NCT00079274

Recruitment Status : Completed

First Posted : March 10, 2004

Results First Posted : February 9, 2015

Last Update Posted : May 13, 2020

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

Participant Flow

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)
Arm/Group Description	Patients received oxaliplatin IV ov...	Patients received irinotecan IV ove...	Patients received the same treatmen...	Patients received cetuximab IV over...	Patients received cetuximab as in a...	Patients received cetuximab as in a...	Patients determined to have mutated...
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
Other	43	7	5	55	1	2	0

Baseline Characteristics

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
Arm/Group Description		Patients received oxaliplatin IV ov...	Patients received irinotecan IV ove...	Patients received the same treatmen...	Patients received cetuximab IV over...	Patients received cetuximab as in a...	Patients received cetuximab as in a...	Patients determined to have mutated...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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

Outcome Measures

1.Primary Outcome


Title	Disease-free Survival (Arms A and D: Wild-type KRAS Patients)
Description	The primary endpoint for...
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

Outcome Measure Data

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
Arm/Group Description:	Patients from Arm A (and a few pati...	Patients from Arm D (and a few pati...
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)
Description	A secondary endpoint for...
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

Outcome Measure Data

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
Arm/Group Description:	Patients from Arm A (and a few pati...	Patients from Arm D (and a few pati...
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)
Description	Evidence of death from any cause within 3 years counted as events in t...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Wild-type KRAS Arm A	Wild-type KRAS Arm D
Arm/Group Description:	Patients from Arm A (and a few pati...	Patients from Arm D (and a few pati...
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)

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)
Description	Evidence of death from any cause within 3 years counted as events in t...
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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Mutant KRAS Arm A	Mutant KRAS Arm D
Arm/Group Description:	Patients from Arm A (and a few pati...	Patients from Arm D (and a few pati...
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)

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)
Description	The maximum grade for each type of toxicity will be recorded for each ...
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

Outcome Measure Data

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
Arm/Group Description:	Patients from Arm A (and a few pati...	Patients from Arm D (and a few pati...
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

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)
Description	The maximum grade for each type of toxicity will be recorded for each ...
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

Outcome Measure Data

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
Arm/Group Description:	Patients from Arm A (and a few pati...	Patients from Arm D (and a few pati...
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

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

Adverse Events

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)
Arm/Group Description	Patients receive oxaliplatin IV ove...		Patients receive irinotecan IV over...		Patients receive the same treatment...		Patients receive cetuximab IV over ...		Patients receive cetuximab as in ar...		Patients receive cetuximab as in ar...		Patients determined to have mutated...
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	--/--		--/--		--/--		--/--		--/--		--/--		--/--
Serious Adverse Events 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
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%)	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
Serum phosphate decreased ^† 1	2/1378 (0.15%)	3	0/108 (0.00%)	0	0/108 (0.00%)	0	9/1326 (0.68%)	13	0/42 (0.00%)	0	1/44 (2.27%)	2	0/0	0
Serum potassium decreased ^† 1	33/1378 (2.39%)	43	2/108 (1.85%)	3	1/108 (0.93%)	1	84/1326 (6.33%)	120	0/42 (0.00%)	0	2/44 (4.55%)	2	0/0	0
Serum potassium increased ^† 1	2/1378 (0.15%)