Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) in Combination With mFOLFOX-6 or FOLFOXIRI in Patients With Metastatic Colorectal Cancer. (NCT NCT00778102)

Last Updated: 2016-11-02

Results Overview

Following resective surgery, participants were evaluated for complete resection (R0) or the presence of microscopic (R1) or macroscopic (R2) residual tumor. The percentage of participants within each residual tumor classification was calculated as \[number of participants with R0, R1, and/or R2 divided by the total number of participants\] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

80 participants

Primary outcome timeframe

Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)

Results posted on

2016-11-02

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab + mFOLFOX-6 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (mFOLFOX-6). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion; oxaliplatin 85 milligrams per meter-squared (mg/m\^2) via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, progressive disease (PD), unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, irinotecan, leucovorin, and 5-FU (FOLFOXIRI). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Overall Study STARTED	39	41
Overall Study COMPLETED	18	19
Overall Study NOT COMPLETED	21	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab + mFOLFOX-6 Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (mFOLFOX-6). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion; oxaliplatin 85 milligrams per meter-squared (mg/m\^2) via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, progressive disease (PD), unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI Participants received a chemotherapy regimen of bevacizumab plus oxaliplatin, irinotecan, leucovorin, and 5-FU (FOLFOXIRI). Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Overall Study Adverse Event	8	5
Overall Study Death	1	1
Overall Study Lost to Follow-up	1	0
Overall Study Violation of Selection Criteria	1	1
Overall Study Protocol Violation	0	1
Overall Study Refused Treatment	2	3
Overall Study Withdrawal by Subject	1	1
Overall Study Administrative Reason	7	10

Baseline Characteristics

A Study of Avastin (Bevacizumab) in Combination With mFOLFOX-6 or FOLFOXIRI in Patients With Metastatic Colorectal Cancer.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Total n=80 Participants Total of all reporting groups
Age, Continuous	57.1 years STANDARD_DEVIATION 10.32 • n=5 Participants	61.8 years STANDARD_DEVIATION 11.02 • n=7 Participants	59.5 years STANDARD_DEVIATION 10.87 • n=5 Participants
Gender Female	21 Participants n=5 Participants	12 Participants n=7 Participants	33 Participants n=5 Participants
Gender Male	18 Participants n=5 Participants	29 Participants n=7 Participants	47 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)

Population: ITT Population

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor R0, R1, or R2	48.7 percentage of participants Interval 32.4 to 65.2	61.0 percentage of participants Interval 44.5 to 75.8
Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor R0 or R1	33.3 percentage of participants Interval 19.1 to 50.2	51.2 percentage of participants Interval 35.1 to 67.1
Percentage of Participants With Complete Resection or Residual (Microscopic or Macroscopic) Tumor R0	23.1 percentage of participants Interval 11.1 to 39.3	48.8 percentage of participants Interval 32.9 to 64.9

SECONDARY outcome

Timeframe: Up to 5 years (at Screening; prior to each cycle, and within 7 days prior to surgery; and at time of surgery)

Population: ITT Population

Time to resection was defined as the time from randomization to the date of first resective surgery. For participants who did not undergo resective surgery, time to resection was censored at Day 1. Time to resection was estimated by Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Time to Resection	4.4 months Interval 4.1 to 5.8	4.3 months Interval 3.9 to 5.5

SECONDARY outcome

Timeframe: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)

Population: ITT Population; only participants with a histopathological assessment after the first resective surgery were included in the analysis.

At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, where 'Complete response' was considered for those with 0 percent (%) viable tumor cells, 'Major response' for those with 1% to 49% viable tumor cells, 'Minor response' for 50% to 99% viable tumor cells, and 'No response' for 100% viable tumor cells. The response could not be determined in some cases and was documented as 'Unknown.' The percentage of participants within each response category was calculated as \[number of participants with a given response divided by the number of participants who completed the assessment\] multiplied by 100.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=14 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=21 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants With Histopathological Response Complete response	0 percentage of participants	4.8 percentage of participants
Percentage of Participants With Histopathological Response Major response	57.1 percentage of participants	47.6 percentage of participants
Percentage of Participants With Histopathological Response Minor response	28.6 percentage of participants	33.3 percentage of participants
Percentage of Participants With Histopathological Response No response	0 percentage of participants	0 percentage of participants
Percentage of Participants With Histopathological Response Unknown	14.3 percentage of participants	14.3 percentage of participants

SECONDARY outcome

Timeframe: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; and at time of/after surgery)

Population: ITT Population; only participants with a histopathological assessment after the first resective surgery were included in the analysis.

At the time of resective surgery, participants were evaluated for histopathological response as defined through pathologist review of the resected metastatic lesions, including assessment of margin status and tumor cell viability. Histopathological response classification was based upon the percentage of viable tumor cells, as described previously. The collective percentage of participants assessed as having a complete or major response was calculated as \[number of participants with complete or major response divided by the number of participants who completed the assessment\] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=14 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=21 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants With Complete or Major Histopathological Response	57.1 percentage of participants Interval 28.9 to 82.3	52.4 percentage of participants Interval 29.8 to 74.3

SECONDARY outcome

Timeframe: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)

Population: ITT Population; only participants with a residual tumor classification of R0 or R1 after first resection were included in the analysis.

Among participants with curative resection (complete resection \[R0\] or microscopic residual tumor \[R1\]), relapse was defined as the first new occurrence of cancer or death. The percentage of participants who experienced relapse was calculated as \[number of participants with a relapse event divided by the number of participants initially classified as R0 or R1 following resective surgery\] multiplied by 100.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=13 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=21 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants Experiencing Relapse Following Curative Resection	76.9 percentage of participants	57.1 percentage of participants

SECONDARY outcome

Timeframe: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)

Population: ITT Population; only participants with a residual tumor classification of R0 or R1 after first resection were included in the analysis.

RFS was defined as the time from curative resection (complete resection \[R0\] or microscopic residual tumor \[R1\]) to the date of first diagnosis of relapse. For participants with curative resection and without relapse, RFS was censored at the last known relapse-free assessment. RFS was estimated by Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=13 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=21 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Relapse-Free Survival (RFS)	8.1 months Interval 3.8 to 11.7	17.1 months Interval 12.3 to Confidence interval upper limit was not reached due to insufficient follow-up.

SECONDARY outcome

Timeframe: Up to 5 years (at Screening; every 6 weeks, and within 4 weeks prior to surgery; 4 and 12 weeks after surgery; and at the end of Cycles 4 and 8 if assessed as R0 or R1, or every 6 weeks until progression or resectability if assessed as R2)

Population: ITT Population

PD was defined, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. The percentage of participants experiencing PD or death was calculated as \[number of participants with event divided by the number of participants analyzed\] multiplied by 100.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants Experiencing Death or Disease Progression	89.7 percentage of participants	68.3 percentage of participants

SECONDARY outcome

Population: ITT Population

PFS was defined, using RECIST version 1.0, as the time from randomization to the date of first documented PD or death from any cause. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. For participants without documented PD or death, PFS was censored at the time of last tumor assessment. PFS was estimated by Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Progression-Free Survival (PFS)	11.5 months Interval 9.6 to 13.6	18.6 months Interval 12.9 to 22.3

SECONDARY outcome

Timeframe: Up to 5 years (prior to each cycle, and within 7 days prior to surgery; at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)

Population: ITT Population

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants Who Died	48.7 percentage of participants	19.5 percentage of participants

SECONDARY outcome

Population: ITT Population

OS was defined as the time from randomization to death from any cause. For participants without an event of death, OS was censored at the last-known alive date. OS was estimated by Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Overall Survival (OS)	32.2 months Interval 21.5 to Confidence interval upper limit was not reached due to insufficient follow-up.	NA months Median and corresponding confidence interval were not reached due to insufficient follow-up.

SECONDARY outcome

Population: ITT Population

Using RECIST version 1.0, participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. The collective percentage of participants with confirmed best overall response of CR or PR was calculated as \[number of participants meeting RECIST criteria for CR or PR divided by the number of participants analyzed\] multiplied by 100. Associated 95% confidence intervals were calculated for one-sample binomial using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.0	61.5 percentage of participants Interval 44.6 to 76.6	80.5 percentage of participants Interval 65.1 to 91.2

SECONDARY outcome

Population: ITT Population

Time to response according to RECIST version 1.0 was defined as the time from randomization to the date of first documented CR or PR. Participants were considered to have achieved CR upon the disappearance of all target and non-target lesions. Participants who achieved PR demonstrated at least a 30% decrease in the sum of the largest diameter of target lesions, taking as reference the Screening sum largest diameter. Responses were confirmed by repeat assessments no less than 4 weeks after criteria for response were first met. For participants who did not complete a confirmatory tumor assessment, time to response was censored at the date of last tumor assessment, or if unavailable, at the date of first dose. Time to response was estimated by Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=39 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=41 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Time to Response	3.1 months Interval 2.7 to 8.6	3.1 months Interval 1.9 to 3.9

SECONDARY outcome

Timeframe: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)

Population: Safety Population (First Surgery Subpopulation): All participants who underwent a first resective surgery and who received at least one dose of trial medication, whether prematurely withdrawn or not. Participants were analyzed according to the actual treatment they received.

Complications related to the first resective surgery were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 equals (=) resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given adverse event (AE) by severity grade was calculated as \[number of participants with an AE divided by the number of participants who underwent first resective surgery\] multiplied by 100.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=19 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=25 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants With Complications Related to First Resective Surgery Any complication, Total	73.7 percentage of participants	52.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Any complication, Grade 1	15.8 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Any complication, Grade 2	36.8 percentage of participants	12.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Any complication, Grade 3	10.5 percentage of participants	24.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Any complication, Grade 4	0 percentage of participants	12.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Any complication, Grade 5	10.5 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Bleeding, Total	15.8 percentage of participants	8.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Bleeding, Grade 1	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Bleeding, Grade 2	5.3 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Bleeding, Grade 3	5.3 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Cardiovascular, Total	10.5 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Cardiovascular, Grade 2	0 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Cardiovascular, Grade 3	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Cardiovascular, Grade 4	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Infections, Total	26.3 percentage of participants	32.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Infections, Grade 1	10.5 percentage of participants	12.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Infections, Grade 2	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Infections, Grade 3	5.3 percentage of participants	16.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Infections, Grade 4	5.3 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Liver insufficiency, Total	10.5 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Liver insufficiency, Grade 5	10.5 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Neural disorder, Total	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Neural disorder, Grade 2	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Noninfected perihepatic fluid collections, Total	0 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Noninfected perihepatic fluid collections, Grade 2	0 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Other complication, Total	52.6 percentage of participants	28.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Other complication, Grade 1	26.3 percentage of participants	8.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Other complication, Grade 2	21.1 percentage of participants	8.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Other complication, Grade 3	0 percentage of participants	12.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Other complication, Grade 4	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Pulmonary, Total	5.3 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Pulmonary, Grade 3	5.3 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Renal impairment, Total	10.5 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Renal impairment, Grade 2	5.3 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Renal impairment, Grade 4	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Wound healing, Total	5.3 percentage of participants	12.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Wound healing, Grade 1	5.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Wound healing, Grade 3	0 percentage of participants	4.0 percentage of participants
Percentage of Participants With Complications Related to First Resective Surgery Wound healing, Grade 4	0 percentage of participants	8.0 percentage of participants

SECONDARY outcome

Timeframe: Up to 5 years (at time of surgery; 48 hours and 4 and 12 weeks after surgery; within 4 weeks after completion of treatment; every 3 to 6 months for 1 year; then annually)

Population: Safety Population (Second Surgery Subpopulation): All participants who underwent a second resective surgery and who received at least one dose of trial medication, whether prematurely withdrawn or not. Participants were analyzed according to the actual treatment they received.

Complications related to the second resective surgery were evaluated using the NCI-CTCAE version 3.0, and classified according to severity. The NCI-CTCAE severity classification criteria are as follows: Grade 5 = resulting in death; Grade 4 = life-threatening; Grade 3 = severe; Grade 2 = moderate; and Grade 1 = mild. The percentage of participants experiencing a given AE by severity grade was calculated as \[number of participants with an AE divided by the number of participants who underwent second resective surgery\] multiplied by 100.

Outcome measures

Outcome measures
Measure	Bevacizumab + mFOLFOX-6 n=3 Participants Participants received a chemotherapy regimen of bevacizumab plus mFOLFOX-6. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; leucovorin 400 mg/m\^2 via IV infusion; 5-FU 400 mg/m\^2 via IV bolus; and 5-FU 2400 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants could discontinue oxaliplatin and continue with bevacizumab, leucovorin, and 5-FU. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.	Bevacizumab + FOLFOXIRI n=3 Participants Participants received a chemotherapy regimen of bevacizumab plus FOLFOXIRI. Each drug was administered on Day 1 of each 2-week cycle. Dosing was as follows: bevacizumab 5 mg/kg via IV infusion; oxaliplatin 85 mg/m\^2 via IV infusion; irinotecan 165 mg/m\^2 via IV infusion; leucovorin 200 mg/m\^2 via IV infusion; and 5-FU 3200 mg/m\^2 via continuous 46-hour IV infusion. Following completion of 12 cycles, participants were to discontinue either irinotecan, oxaliplatin, or both. Treatment was continued until resectability, PD, unacceptable toxicity, or participant refusal.
Percentage of Participants With Complications Related to Second Resective Surgery Any complication, Total	100.0 percentage of participants	66.7 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Any complication, Grade 1	0 percentage of participants	33.3 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Any complication, Grade 2	66.7 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Any complication, Grade 3	0 percentage of participants	33.3 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Any complication, Grade 3a	33.3 percentage of participants	0 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Bleeding, Total	33.3 percentage of participants	33.3 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Bleeding, Grade 1	0 percentage of participants	33.3 percentage of participants
Percentage of Participants With Complications Related to Second Resective Surgery Bleeding, Grade 2	33.3 percentage of participants	0 percentage of participants

Adverse Events

Bevacizumab + mFOLFOX-6

Serious events: 24 serious events

Other events: 36 other events

Deaths: 0 deaths

Bevacizumab + FOLFOXIRI

Serious events: 24 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER