Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for High Risk Stage II or Stage III Colon Cancer

This study has been completed.

Sponsor:

Collaborator:

National Cancer Institute (NCI)

Information provided by (Responsible Party):

Hoffmann-La Roche

ClinicalTrials.gov Identifier:

NCT00112918

First received: June 2, 2005

Last updated: August 6, 2012

Last verified: August 2012

History of Changes

Results First Received: June 1, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Colorectal Cancer
Interventions:	Biological: Bevacizumab Drug: Capecitabine Drug: 5-Fluorouracil (5-FU) Drug: Leucovorin calcium Drug: Oxaliplatin

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Randomization was stratified according to geographic region and disease stage (high-risk stage II or stage III N1 or stage III N2). The primary analysis population consisted of patients with Stage III disease.

Reporting Groups

Description

FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 1–24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 1–24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Participant Flow: Overall Study

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv
STARTED	1151	1155	1145
Received Treatment	1126	1145 ^[1]	1135
Stage III Disease Population	955	960	952
COMPLETED	937 ^[2]	917 ^[2]	916 ^[2]
NOT COMPLETED	214	238	229

[1]	Includes two patients from FOLFOX4 who received Bv and were assigned to FOLFOX4+Bv safety analysis
[2]	Represents patients alive in follow-up at the time of data cut-off (30 June 2010)

Baseline Characteristics

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Reporting Groups

	Description
FOLFOX4	Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.
FOLFOX4 + Bv	Weeks 1–24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
XELOX+Bv	Weeks 1–24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
Total	Total of all reporting groups

Baseline Measures

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv	Total
Number of Participants [units: participants]	955	960	952	2867
Age, Customized ^[1] [units: participants]
<40	77	74	68	219
40-65	603	625	588	1816
>=65	275	261	296	832
Gender [units: participants]
Female	425	473	432	1330
Male	530	487	520	1537
Race/Ethnicity, Customized [units: participants]
American Indian or Alaska Native	1	1	0	2
Asian	139	115	123	377
Black or African American	6	13	14	33
White	791	813	795	2399
Other	18	18	20	56

[1]	Baseline Measures are based on the Intent-to-Treat - Stage III Disease Patient Population.

Outcome Measures

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1. Primary:

Disease-free Survival in Stage III Cancer Patients - Time to Event [ Time Frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

Measure Type	Primary
Measure Title	Disease-free Survival in Stage III Cancer Patients - Time to Event
Measure Description	Disease-free survival (DFS) was defined as the time from the date of randomization to the time of a recurrence, a new occurrence of colorectal cancer or death due to any cause, whichever occurred first. Patients without an event were censored at the last date the patient was known to be disease-free. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Patients with no tumor assessments after baseline but still alive at the time of the clinical cut-off were censored at day 1.
Time Frame	From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The primary population for efficacy analyses was the intent to treat population (ITT; all randomized patients) with stage III disease.

Reporting Groups

	Description
FOLFOX4	Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.
FOLFOX4 + Bv	Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
XELOX+Bv	Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Description

FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks).

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Measured Values

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv
Number of Participants Analyzed [units: participants]	955	960	952
Disease-free Survival in Stage III Cancer Patients - Time to Event [units: months] Median ( 95% Confidence Interval )	NA ( NA to NA ) ^[1]	NA ( NA to NA ) ^[1]	NA ( NA to NA ) ^[1]

[1]	Median time to event and 95% confidence intervals could not be estimated due to the low number of events.

Statistical Analysis 1 for Disease-free Survival in Stage III Cancer Patients - Time to Event

Groups ^[1]	All groups
Method ^[2]	Closed test procedure
P Value ^[3]	0.2024

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Adjustments for multiplicity was done using a closed test procedure which tests for differences between all three treatment groups at the 5% alpha level first. Only in case of a significant result, the pair-wise comparison between the control arm and each of the bevacizumab arm will be tested, again at the 5% alpha level.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

2. Primary:

Disease-free Survival in Stage III Cancer Patients - Number of Events [ Time Frame: From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

Measure Type	Primary
Measure Title	Disease-free Survival in Stage III Cancer Patients - Number of Events
Measure Description	A disease-free survival (DFS) event was composed of a recurrence, a new occurrence of colorectal cancer or death due to any cause. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Triggering events for DFS are reported; a patient can have both recurrence and a new occurrence of colon cancer.
Time Frame	From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The primary population for efficacy analyses was the intent to treat population (ITT; all randomized patients) with stage III disease.

Reporting Groups

	Description
FOLFOX4	Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.
FOLFOX4 + Bv	Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
XELOX+Bv	Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Description

FOLFOX4

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Measured Values

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv
Number of Participants Analyzed [units: participants]	955	960	952
Disease-free Survival in Stage III Cancer Patients - Number of Events [units: participants]
Patients with a DFS event	237	280	253
Recurrence	219	253	223
New Occurrence	3	8	6
Death	17	21	25
Patients without events	718	680	699

No statistical analysis provided for Disease-free Survival in Stage III Cancer Patients - Number of Events

3. Secondary:

Overall Survival in Stage III Cancer Patients - Time to Event [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

Measure Type	Secondary
Measure Title	Overall Survival in Stage III Cancer Patients - Time to Event
Measure Description	Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the analysis were censored at the date they were last known to be alive.
Time Frame	From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT patients with Stage III disease.

Reporting Groups

	Description
FOLFOX4	Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.
FOLFOX4 + Bv	Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
XELOX+Bv	Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Description

FOLFOX4

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Measured Values

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv
Number of Participants Analyzed [units: participants]	955	960	952
Overall Survival in Stage III Cancer Patients - Time to Event [units: months] Median ( 95% Confidence Interval )	NA ( NA to NA ) ^[1]	NA ( NA to NA ) ^[1]	NA ( NA to NA ) ^[1]

[1]	Median time to event and 95% confidence intervals could not be estimated due to the low number of events.

No statistical analysis provided for Overall Survival in Stage III Cancer Patients - Time to Event

4. Secondary:

Overall Survival in Stage III Cancer Patients - Number of Events [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]

Measure Type	Secondary
Measure Title	Overall Survival in Stage III Cancer Patients - Number of Events
Measure Description	An overall survival event was death due to any cause.
Time Frame	From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT patients with Stage III disease.

Reporting Groups

	Description
FOLFOX4	Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.
FOLFOX4 + Bv	Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
XELOX+Bv	Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Description

FOLFOX4

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Measured Values

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv
Number of Participants Analyzed [units: participants]	955	960	952
Overall Survival in Stage III Cancer Patients - Number of Events [units: participants]
Patients with events	115	151	145
Patients without events	840	809	807

No statistical analysis provided for Overall Survival in Stage III Cancer Patients - Number of Events

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Hide Other Adverse Events

Time Frame	All adverse events occurring between the date of first drug intake and 28 days after last drug intake, regardless of which treatment group the patient was randomized to.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
FOLFOX4	Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with Leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only.
FOLFOX4 + Bv	Weeks 1–24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).
XELOX+Bv	Weeks 1–24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 – 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Description

FOLFOX4

Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with Leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks).

Weeks 25-48: Observation only.

FOLFOX4 + Bv

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

XELOX+Bv

Weeks 25–48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks).

Other Adverse Events

	FOLFOX4	FOLFOX4 + Bv	XELOX+Bv
Total, other (not including serious) adverse events
# participants affected / at risk	1112/1126	1127/1145	1117/1135
Blood and lymphatic system disorders
Neutropenia ^{† 1}
# participants affected / at risk	660/1126 (58.61%)	567/1145 (49.52%)	273/1135 (24.05%)
Thrombocytopenia ^{† 1}
# participants affected / at risk	331/1126 (29.40%)	115/1145 (10.04%)	99/1135 (8.72%)
Anaemia ^{† 1}
# participants affected / at risk	116/1126 (10.30%)	89/1145 (7.77%)	74/1135 (6.52%)
Leukopenia ^{† 1}
# participants affected / at risk	79/1126 (7.02%)	55/1145 (4.80%)	34/1135 (3.00%)
Eye disorders
Lacrimation increased ^{† 1}
# participants affected / at risk	70/1126 (6.22%)	69/1145 (6.03%)	35/1135 (3.08%)
Gastrointestinal disorders
Nausea ^{† 1}
# participants affected / at risk	725/1126 (64.39%)	761/1145 (66.46%)	720/1135 (63.44%)
Diarrhoea ^{† 1}
# participants affected / at risk	620/1126 (55.06%)	699/1145 (61.05%)	699/1135 (61.59%)
Vomiting ^{† 1}
# participants affected / at risk	385/1126 (34.19%)	394/1145 (34.41%)	460/1135 (40.53%)
Stomatitis ^{† 1}
# participants affected / at risk	310/1126 (27.53%)	360/1145 (31.44%)	246/1135 (21.67%)
Constipation ^{† 1}
# participants affected / at risk	308/1126 (27.35%)	324/1145 (28.30%)	219/1135 (19.30%)
Abdominal pain ^{† 1}
# participants affected / at risk	220/1126 (19.54%)	227/1145 (19.83%)	214/1135 (18.85%)
Dyspepsia ^{† 1}
# participants affected / at risk	126/1126 (11.19%)	162/1145 (14.15%)	84/1135 (7.40%)
Abdominal pain upper ^{† 1}
# participants affected / at risk	86/1126 (7.64%)	118/1145 (10.31%)	113/1135 (9.96%)
Haemorrhoids ^{† 1}
# participants affected / at risk	29/1126 (2.58%)	68/1145 (5.94%)	41/1135 (3.61%)
General disorders
Fatigue ^{† 1}
# participants affected / at risk	404/1126 (35.88%)	425/1145 (37.12%)	355/1135 (31.28%)
Asthenia ^{† 1}
# participants affected / at risk	241/1126 (21.40%)	251/1145 (21.92%)	250/1135 (22.03%)
Pyrexia ^{† 1}
# participants affected / at risk	186/1126 (16.52%)	185/1145 (16.16%)	106/1135 (9.34%)
Mucosal inflammation ^{† 1}
# participants affected / at risk	85/1126 (7.55%)	85/1145 (7.42%)	57/1135 (5.02%)
Temperature intolerance ^{† 1}
# participants affected / at risk	61/1126 (5.42%)	61/1145 (5.33%)	50/1135 (4.41%)
Oedema peripheral ^{† 1}
# participants affected / at risk	54/1126 (4.80%)	62/1145 (5.41%)	45/1135 (3.96%)
Immune system disorders
Drug hypersensitivity ^{† 1}
# participants affected / at risk	66/1126 (5.86%)	72/1145 (6.29%)	32/1135 (2.82%)
Infections and infestations
Nasopharyngitis ^{† 1}
# participants affected / at risk	76/1126 (6.75%)	92/1145 (8.03%)	70/1135 (6.17%)
Upper respiratory tract infection ^{† 1}
# participants affected / at risk	52/1126 (4.62%)	87/1145 (7.60%)	55/1135 (4.85%)
Investigations
Weight increased ^{† 1}
# participants affected / at risk	58/1126 (5.15%)	81/1145 (7.07%)	68/1135 (5.99%)
Weight decreased ^{† 1}
# participants affected / at risk	26/1126 (2.31%)	56/1145 (4.89%)	61/1135 (5.37%)
Metabolism and nutrition disorders
Decreased appetite ^{† 1}
# participants affected / at risk	268/1126 (23.80%)	324/1145 (28.30%)	295/1135 (25.99%)
Musculoskeletal and connective tissue disorders
Arthralgia ^{† 1}
# participants affected / at risk	63/1126 (5.60%)	140/1145 (12.23%)	122/1135 (10.75%)
Pain in extremity ^{† 1}
# participants affected / at risk	63/1126 (5.60%)	78/1145 (6.81%)	116/1135 (10.22%)
Back pain ^{† 1}
# participants affected / at risk	79/1126 (7.02%)	87/1145 (7.60%)	66/1135 (5.81%)
Musculoskeletal pain ^{† 1}
# participants affected / at risk	35/1126 (3.11%)	86/1145 (7.51%)	46/1135 (4.05%)
Myalgia ^{† 1}
# participants affected / at risk	39/1126 (3.46%)	70/1145 (6.11%)	56/1135 (4.93%)
Nervous system disorders
Peripheral sensory neuropathy ^{† 1}
# participants affected / at risk	430/1126 (38.19%)	430/1145 (37.55%)	436/1135 (38.41%)
Paraesthesia ^{† 1}
# participants affected / at risk	310/1126 (27.53%)	328/1145 (28.65%)	314/1135 (27.67%)
Neuropathy peripheral ^{† 1}
# participants affected / at risk	252/1126 (22.38%)	234/1145 (20.44%)	204/1135 (17.97%)
Headache ^{† 1}
# participants affected / at risk	169/1126 (15.01%)	284/1145 (24.80%)	219/1135 (19.30%)
Dysgeusia ^{† 1}
# participants affected / at risk	237/1126 (21.05%)	222/1145 (19.39%)	152/1135 (13.39%)
Dysaesthesia ^{† 1}
# participants affected / at risk	128/1126 (11.37%)	106/1145 (9.26%)	128/1135 (11.28%)
Dizziness ^{† 1}
# participants affected / at risk	102/1126 (9.06%)	117/1145 (10.22%)	79/1135 (6.96%)
Neurotoxicity ^{† 1}
# participants affected / at risk	60/1126 (5.33%)	69/1145 (6.03%)	50/1135 (4.41%)
Lethargy ^{† 1}
# participants affected / at risk	44/1126 (3.91%)	50/1145 (4.37%)	59/1135 (5.20%)
Psychiatric disorders
Insomnia ^{† 1}
# participants affected / at risk	135/1126 (11.99%)	132/1145 (11.53%)	91/1135 (8.02%)
Anxiety ^{† 1}
# participants affected / at risk	45/1126 (4.00%)	60/1145 (5.24%)	61/1135 (5.37%)
Renal and urinary disorders
Proteinuria ^{† 1}
# participants affected / at risk	19/1126 (1.69%)	73/1145 (6.38%)	69/1135 (6.08%)
Respiratory, thoracic and mediastinal disorders
Epistaxis ^{† 1}
# participants affected / at risk	228/1126 (20.25%)	424/1145 (37.03%)	216/1135 (19.03%)
Cough ^{† 1}
# participants affected / at risk	86/1126 (7.64%)	120/1145 (10.48%)	41/1135 (3.61%)
Dyspnoea ^{† 1}
# participants affected / at risk	57/1126 (5.06%)	74/1145 (6.46%)	73/1135 (6.43%)
Dysphonia ^{† 1}
# participants affected / at risk	17/1126 (1.51%)	91/1145 (7.95%)	74/1135 (6.52%)
Dysaesthesia pharynx ^{† 1}
# participants affected / at risk	37/1126 (3.29%)	28/1145 (2.45%)	79/1135 (6.96%)
Oropharyngeal pain ^{† 1}
# participants affected / at risk	52/1126 (4.62%)	59/1145 (5.15%)	33/1135 (2.91%)
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome ^{† 1}
# participants affected / at risk	98/1126 (8.70%)	119/1145 (10.39%)	435/1135 (38.33%)
Alopecia ^{† 1}
# participants affected / at risk	231/1126 (20.52%)	241/1145 (21.05%)	73/1135 (6.43%)
Rash ^{† 1}
# participants affected / at risk	114/1126 (10.12%)	112/1145 (9.78%)	110/1135 (9.69%)
Dry skin ^{† 1}
# participants affected / at risk	52/1126 (4.62%)	66/1145 (5.76%)	50/1135 (4.41%)
Pruritus ^{† 1}
# participants affected / at risk	36/1126 (3.20%)	65/1145 (5.68%)	28/1135 (2.47%)
Vascular disorders
Hypertension ^{† 1}
# participants affected / at risk	196/1126 (17.41%)	472/1145 (41.22%)	468/1135 (41.23%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (13.0)

More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Medical Communications
Organization: Hoffman-LaRoche
phone: 800-821-8590

No publications provided by Hoffmann-La Roche

Publications automatically indexed to this study:

de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. doi: 10.1016/S1470-2045(12)70509-0. Epub 2012 Nov 16.

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00112918 History of Changes
Other Study ID Numbers:	CDR0000427299, P30CA016042, UCLA-0412086-01, ROCHE-BO17920A
Study First Received:	June 2, 2005
Results First Received:	June 1, 2012
Last Updated:	August 6, 2012
Health Authority:	United States: Food and Drug Administration

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