Colorectal Cancer
Conditions
Brief summary
This 4 arm study assessed the efficacy and safety of oral capecitabine (Xeloda) or intravenous (iv) fluorouracil/leucovorin, in combination with iv oxaliplatin (Eloxatin) with or without iv bevacizumab (Avastin), as a first-line treatment in patients with metastatic colorectal cancer. Patients were randomized to receive 1) XELOX (Xeloda 1000 mg/m\^2 orally \[po\] twice a day \[bid\] on Days 1-15 + oxaliplatin in 3 week cycles), 2) FOLFOX-4 (oxaliplatin + leucovorin + fluorouracil \[5-FU\] in 2 week cycles), 3) XELOX + bevacizumab (7.5 mg iv on Day 1 in 3 week cycles), or 4) FOLFOX-4 + bevacizumab (5 mg iv on Day 1 in 2 week cycles).
Detailed description
This study was conducted in 2 parts: An initial 2-arm part in which patients were randomized to 1 of 2 different treatment groups (XELOX or FOLFOX-4), and a subsequent 2 x 2 factorial part, added to the study through a protocol amendment, in which additional patients were randomized into one of 4 different treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + bevacizumab, or FOLFOX-4 + bevacizumab). Due to the comparison of the oral agent capecitabine with bolus and infused fluorouracil, the study was not blinded with respect to these 2 treatments. The study was double-blind with regard to the administration of bevacizumab, ie, there was a placebo control for bevacizumab in the second part of the study. The study consisted of 3 phases, a Primary Study Treatment Phase, a Post-Study Treatment Phase, and a Follow-Up Phase. Primary Study Treatment Phase Patients were to receive up to 16 cycles (2-arm part of the study) or 24 cycles (4-arm part of the study) of treatment during the Primary Study Treatment Phase (48 weeks). Post-Study Treatment Phase Patients who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Patients who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the patient withdrew consent. Follow-up Phase Patients who terminated study treatment during the primary or post-study treatment phase were followed until disease progression or death.
Interventions
DRUGPlacebo for bevacizumab 5 mg/kg
Placebo control for bevacizumab (volume equivalent to 5 mg/kg bevacizumab) was administered in a 30 to 90 min infusion.
DRUGOxaliplatin 130 mg/m^2
Oxaliplatin was administered in a 2 h infusion before the first dose of capecitabine.
DRUGCapecitabine 1000 mg/m^2
Capecitabine was taken within 30 min after the end of breakfast and dinner.
Bevacizumab was administered in a 30 to 90 min infusion.
DRUGPlacebo for bevacizumab 7.5 mg/kg
Placebo control for bevacizumab (volume equivalent to 7.5 mg/kg bevacizumab) was administered in a 30 to 90 min infusion.
Oxaliplatin 85 mg/m\^2 was administered simultaneously with leucovorin in a 2 h infusion.
DRUGLeucovorin 200 mg/m^2
Leucovorin was administered simultaneously with oxaliplatin 85 mg/m\^2 in a 2 h infusion.
DRUGFluorouracil 400 mg/m^2
Bevacizumab was administered in a 30 to 90 min infusion.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients ≥ 18 years of age. * Metastatic colorectal cancer. * ≥ 1 target lesion.
Exclusion criteria
* Previous treatment with oxaliplatin or bevacizumab. * Previous systemic chemotherapy or immunotherapy for advanced or metastatic disease. * Progressive disease during or within 6 months of completion of previous adjuvant therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Baseline until disease progression or death, approximately 2 years 6 months | PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4 | Baseline until disease progression or death, approximately 2 years 6 months | PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4- containing arms was investigated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 1 to Week 54 | For participants whose BOR was CR or PR, time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status was recorded first) was met. It was based on tumor assessments made by the investigators according to the RECIST criteria. Results were reported as the number of participants achieving a response in 8 time categories from Week 1 to Week 54. Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | From baseline until disease progression/recurrence, approximately 2 years 6 months | Duration of overall response was measured from the time that measurement criteria were first met for CR or PR (whichever status was recorded first) until the first date when progressive disease or death was documented. It was based on tumor assessments made by the investigators according to the RECIST criteria. Participants who neither progressed nor died were censored at the date of the last tumor assessment. Participants undergoing surgical resection with curative intent were censored at the date of surgery. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone | From baseline until disease progression/recurrence, approximately 2 years 6 months | Duration of overall response was measured from the time that measurement criteria were first met for CR or PR (whichever status was recorded first) until the first date when progressive disease or death was documented. It was based on tumor assessments made by the investigators according to the RECIST criteria. Participants who neither progressed nor died were censored at the date of the last tumor assessment. Participants undergoing surgical resection with curative intent were censored at the date of surgery. Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | From baseline until disease progression/recurrence, approximately 2 years 6 months | For complete responders, the duration of complete response was measured from the time measurement criteria were first met for complete response until the date that progressive disease (or death) was documented. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | From baseline until disease progression/recurrence, approximately 2 years 6 months | For complete responders, the duration of complete response was measured from the time measurement criteria were first met for complete response until the date that progressive disease (or death) was documented. Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4 | Baseline until disease progression or death, approximately 2 years 6 months | PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the IRC. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Baseline until disease progression or death, approximately 2 years 6 months | PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the IRC. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the bevacizumab-containing arms was compared with the placebo-containing arms. |
| PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4 | Baseline until disease progression or death, approximately 2 years 6 months | PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. The on-treatment analysis included only tumor assessments and death events that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase. Participants who did not have an event during this interval were censored at the date of the last tumor assessment within this time window, or on day 1 if no tumor assessment was available after baseline. Participants who underwent surgical resection with curative intent without prior progression within 28 days after the last confirmed intake of any study medication in the primary study treatment phase were censored at the date of surgery. The on-treatment approach excluded the possible impact of other treatments that might have been started before disease progression. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Baseline until disease progression or death, approximately 2 years 6 months | PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. The on-treatment analysis included only tumor assessments and death events that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase. Participants who did not have an event during this interval were censored at the date of the last tumor assessment within this time window, or on day 1 if no tumor assessment was available after baseline. Participants who underwent surgical resection with curative intent without prior progression within 28 days after the last confirmed intake of any study medication in the primary study treatment phase were censored at the date of surgery. The on-treatment approach excluded the possible impact of other treatments that might have been started before disease progression. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4 | Baseline until disease progression or death, approximately 2 years 6 months | PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants who underwent curative surgery after experiencing a sufficient shrinkage of their tumor were not censored at the date of surgery, but any relapse, new occurrence of colorectal cancer, or death was considered as an event. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Baseline until disease progression or death, approximately 2 years 6 months | PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants who underwent curative surgery after experiencing a sufficient shrinkage of their tumor were not censored at the date of surgery, but any relapse, new occurrence of colorectal cancer, or death was considered as an event. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4 | Baseline until disease progression or death, approximately 2 years 6 months | Overall survival was defined as the time from the date of randomization to the date of death. Participants who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Baseline until disease progression or death, approximately 2 years 6 months | Overall survival was defined as the time from the date of randomization to the date of death. Participants who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive. Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4 | From baseline until disease progression/recurrence, approximately 2 years 6 months | According to the RECIST criteria, BOR in an individual participant was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments as assessed by the investigator and made up to and including 28 days after last intake of study medication in the primary study treatment phase not later than date of first curative surgery were included in these analyses. Responders were defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | From baseline until disease progression/recurrence, approximately 2 years 6 months | According to the RECIST criteria, BOR in an individual participant was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments as assessed by the investigator and made up to and including 28 days after last intake of study medication in the primary study treatment phase not later than date of first curative surgery were included in these analyses. Responders were defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | From baseline until disease progression/recurrence, approximately 2 years 6 months | According to the RECIST criteria, the BOR in an individual participant was the best response recorded from the start of the treatment until disease progression/recurrence (taking the smallest measurements recorded since the baseline assessment as a reference for PD). The BOR as assessed by the IRC was determined based on tumor assessments that were made up to and including 28 days after last intake of study medication in the primary study treatment phase. Responders were defined as the percentage of participants with a complete response (CR) or partial response (PR). Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
| BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | From baseline until disease progression/recurrence, approximately 2 years 6 months | According to the RECIST criteria, the BOR in an individual participant was the best response recorded from the start of the treatment until disease progression/recurrence (taking the smallest measurements recorded since the baseline assessment as a reference for PD). The BOR as assessed by the IRC was determined based on tumor assessments that were made up to and including 28 days after last intake of study medication in the primary study treatment phase. Responders were defined as the percentage of participants with a complete response (CR) or partial response (PR). Superiority of the BV-containing arms was compared with the chemotherapy alone arms. |
| Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | From baseline until disease progression/recurrence, approximately 2 years 6 months | Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, participant refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurred first. The general approach included all tumor assessments or deaths that occurred during the primary study treatment phase, the post-study treatment phase, or the follow-up phase. The on-treatment approach included only tumor assessments and deaths that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase only. |
| Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | From baseline until disease progression/recurrence, approximately 2 years 6 months | Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, participant refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurred first. The general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase.The on-treatment approach included only tumor assessments and deaths that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase only. |
| Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 1 to Week 54 | For participants whose BOR was CR or PR, time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status was recorded first) was met. It was based on tumor assessments made by the investigators according to the RECIST criteria. Results were reported as the number of participants achieving a response in 8 time categories from Week 1 to Week 54. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms. |
Countries
Australia, Austria, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Mexico, New Zealand, Norway, Panama, Portugal, Puerto Rico, Russia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 32 countries - Australia, Austria, Brazil, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Great Britain, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Korea, Mexico, New Zealand, Norway, Panama, Portugal, Russia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey and USA.
Pre-assignment details
A total of 2035 participants were randomized to any one of the treatment groups in the study (634 participants in the initial 2-arm part and 1401 participants in the 2x2 factorial part of the study), but only 2034 received study treatment as 1 participant was enrolled twice in the study at 2 study centers.
Participants by arm
| Arm | Count |
|---|---|
| Xelox Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 130 mg/m\^2 over 2 hours on Day 1 of every 3 weeks before the first dose of capecitabine. Capecitabine was administered orally within 30 minutes after the end of a meal (breakfast and dinner) at a dose of 1000 mg/m\^2 twice-daily (equivalent to a total daily dose of 2000 mg/m\^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. | 317 |
| Folfox-4 Participants in the 2-arm part of the study received intravenous infusion of oxaliplatin 85 mg/m\^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m\^2 iv for 2 hours followed by fluorouracil 400 mg/m\^2 bolus injection over 2 to 4 min followed by 600 mg/m\^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. | 317 |
| Xelox+P Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for bevacizumab (BV) \[volume equivalent to 7.5 mg/kg BV\] over 30 to 90 minutes followed by oxaliplatin 130 mg/m\^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m\^2 twice-daily (equivalent to a total daily dose of 2000 mg/m\^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. | 350 |
| Folfox-4+P Participants in the 2x2 factorial part of the study received intravenous infusion of placebo control for BV (volume equivalent to 5 mg/kg BV) over 30 to 90 minutes followed by oxaliplatin 85 mg/m\^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m\^2 iv for 2 hours followed by fluorouracil 400 mg/m\^2 bolus injection over 2 to 4 min followed by 600 mg/m\^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. | 351 |
| Xelox+BV Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 7.5 mg/kg over 30 to 90 minutes followed by oxaliplatin 130 mg/m\^2 over 2 hours on Day 1 of every 3 weeks in combination with capecitabine, administered orally at a dose of 1000 mg/m\^2 twice-daily (equivalent to a total daily dose of 2000 mg/m\^2), for the first 2 weeks of every 3-week cycle. Participants received up to 16 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. | 350 |
| Folfox-4+BV Participants in the 2x2 factorial part of the study received intravenous infusion of bevacizumab 5 mg/kg over 30 to 90 minutes followed by oxaliplatin 85 mg/m\^2 on Day 1 of every 2-week cycle; concomitantly with leucovorin 200 mg/m\^2 iv for 2 hours followed by fluorouracil 400 mg/m\^2 bolus injection over 2 to 4 min followed by 600 mg/m\^2 continuous infusion over 22 h on Days 1 and 2 of every 2-week cycle. Participants received up to 24 cycles of treatment during the primary study treatment phase (48 weeks). Participants who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Participants who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the participant withdrew consent. | 349 |
| Total | 2,034 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Follow-up Phase | Death | 174 | 206 | 120 | 112 | 92 | 101 |
| Post-study Treatment Phase | Adverse Event | 2 | 3 | 1 | 0 | 5 | 1 |
| Post-study Treatment Phase | Death | 0 | 0 | 0 | 0 | 1 | 0 |
| Post-study Treatment Phase | Eligible for surgery | 2 | 0 | 0 | 0 | 0 | 0 |
| Post-study Treatment Phase | Insufficient therapeutic response | 1 | 4 | 5 | 6 | 7 | 9 |
| Post-study Treatment Phase | Investigator decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Post-study Treatment Phase | Investigator decision (enough treatment) | 0 | 1 | 1 | 0 | 1 | 0 |
| Post-study Treatment Phase | Missing reason | 1 | 3 | 12 | 8 | 18 | 17 |
| Post-study Treatment Phase | More than 21 days delay between cycles | 0 | 1 | 0 | 0 | 0 | 0 |
| Post-study Treatment Phase | Participant completed treatment | 0 | 0 | 0 | 1 | 0 | 0 |
| Post-study Treatment Phase | Participant had complete response | 1 | 1 | 0 | 0 | 0 | 0 |
| Post-study Treatment Phase | Participant had progressive disease | 0 | 0 | 0 | 0 | 1 | 0 |
| Post-study Treatment Phase | Participant/Physician decision to stop | 0 | 0 | 0 | 0 | 1 | 0 |
| Post-study Treatment Phase | Participant refusal/Admin reasons | 1 | 0 | 0 | 0 | 0 | 1 |
| Post-study Treatment Phase | Participant wanted break from treatment | 0 | 0 | 0 | 1 | 0 | 0 |
| Post-study Treatment Phase | Participant will start new treatment | 0 | 0 | 1 | 0 | 0 | 0 |
| Post-study Treatment Phase | Participant withdrew consent | 0 | 0 | 1 | 0 | 0 | 0 |
| Post-study Treatment Phase | Preplanned 6 cycles after surgery | 0 | 0 | 0 | 0 | 1 | 0 |
| Post-study Treatment Phase | Surgery | 0 | 0 | 0 | 1 | 1 | 0 |
| Primary Treatment Phase | Admin/Other | 29 | 38 | 31 | 45 | 48 | 42 |
| Primary Treatment Phase | Adverse Event | 99 | 92 | 71 | 72 | 109 | 101 |
| Primary Treatment Phase | Death | 14 | 8 | 2 | 5 | 8 | 8 |
| Primary Treatment Phase | Failure to return | 5 | 5 | 0 | 0 | 0 | 2 |
| Primary Treatment Phase | Insufficient Therapeutic Response | 131 | 127 | 175 | 154 | 101 | 102 |
| Primary Treatment Phase | Ongoing | 0 | 0 | 5 | 7 | 7 | 4 |
| Primary Treatment Phase | Other Violation | 0 | 1 | 1 | 1 | 0 | 1 |
| Primary Treatment Phase | Refused treatment | 15 | 26 | 17 | 31 | 24 | 27 |
| Primary Treatment Phase | Violation criteria | 0 | 2 | 4 | 3 | 1 | 5 |
| Primary Treatment Phase | Withdrew | 2 | 3 | 8 | 2 | 4 | 9 |
Baseline characteristics
| Characteristic | Xelox | Folfox-4 | Xelox+P | Folfox-4+P | Xelox+BV | Folfox-4+BV | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 10.76 | 60.6 years STANDARD_DEVIATION 10.94 | 59.1 years STANDARD_DEVIATION 12.14 | 58.8 years STANDARD_DEVIATION 10.87 | 59.7 years STANDARD_DEVIATION 11.28 | 59.7 years STANDARD_DEVIATION 10.74 | 59.7 years STANDARD_DEVIATION 11.14 |
| Sex: Female, Male Female | 123 Participants | 113 Participants | 145 Participants | 165 Participants | 137 Participants | 144 Participants | 827 Participants |
| Sex: Female, Male Male | 194 Participants | 204 Participants | 205 Participants | 186 Participants | 213 Participants | 205 Participants | 1207 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 310 / 316 | 310 / 313 | 330 / 339 | 331 / 336 | 348 / 353 | 335 / 341 |
| serious Total, serious adverse events | 117 / 316 | 120 / 313 | 121 / 339 | 128 / 336 | 131 / 353 | 146 / 341 |
Outcome results
Primary
PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 244.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 285.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: 0.002397.5% CI: [0.72, 0.95]Log Rank
Primary
Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4
PFS was defined as the time from randomization to progressive disease or death. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants with no tumor assessments after baseline who were alive at the time of clinical cutoff were censored at the date of randomization. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was based on tumor assessments made by the investigators according to the RECIST criteria. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4- containing arms was investigated.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The eligible patient population (EPP) excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4 | 259 days |
| XELOX/XELOX+P/XELOX+BV | Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4 | 241 days |
Comparison: Equivalence of treatment arm A ('XELOX') to treatment arm B ('FOLFOX-4') was tested via the following hypotheses - H0: HRA/B \>/= 1.23 versus H1: HRA/B \< 1.23. HRA/B denotes the hazard of disease progression or death under treatment A ('XELOX') divided by the hazard of disease progression or death under treatment B ('FOLFOX-4').97.5% CI: [0.94, 1.18]
Secondary
Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
According to the RECIST criteria, BOR in an individual participant was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments as assessed by the investigator and made up to and including 28 days after last intake of study medication in the primary study treatment phase not later than date of first curative surgery were included in these analyses. Responders were defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 49.2 Percentage of responders |
| XELOX/XELOX+P/XELOX+BV | Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 46.5 Percentage of responders |
Comparison: Superiority of adding bevacizumab to chemotherapy was tested as follows - H0: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX-4+P/XELOX+P) \</= 1.0 versus H1: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX-4+P/XELOX+P) \> 1.0. The test used a two-sided significance level of 2.5%.p-value: 0.309197.5% CI: [0.71, 1.14]Chi-squared
Secondary
Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4
According to the RECIST criteria, BOR in an individual participant was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments as assessed by the investigator and made up to and including 28 days after last intake of study medication in the primary study treatment phase not later than date of first curative surgery were included in these analyses. Responders were defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4 | 49.4 Percentage of responders |
| XELOX/XELOX+P/XELOX+BV | Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4 | 46.4 Percentage of responders |
Comparison: Non-inferiority of XELOX with/without bevacizumab to FOLFOX-4 with/without bevacizumab was tested by the pair of hypotheses - H0: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) \</= 0.66 versus H1: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) \> 0.66, where OR denotes Odds ratio.97.5% CI: [0.72, 1.09]
Secondary
BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
According to the RECIST criteria, the BOR in an individual participant was the best response recorded from the start of the treatment until disease progression/recurrence (taking the smallest measurements recorded since the baseline assessment as a reference for PD). The BOR as assessed by the IRC was determined based on tumor assessments that were made up to and including 28 days after last intake of study medication in the primary study treatment phase. Responders were defined as the percentage of participants with a complete response (CR) or partial response (PR). Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | 38.6 Percentage of responders |
| XELOX/XELOX+P/XELOX+BV | BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | 37.1 Percentage of responders |
Comparison: Non-inferiority of XELOX with/without bevacizumab to FOLFOX-4 with/without bevacizumab was tested by the pair of hypotheses - H0: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) \</= 0.66 versus H1: OR(XELOX/XELOX+P/XELOX+BV)/(FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV) \> 0.6697.5% CI: [0.76, 1.16]
Secondary
BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
According to the RECIST criteria, the BOR in an individual participant was the best response recorded from the start of the treatment until disease progression/recurrence (taking the smallest measurements recorded since the baseline assessment as a reference for PD). The BOR as assessed by the IRC was determined based on tumor assessments that were made up to and including 28 days after last intake of study medication in the primary study treatment phase. Responders were defined as the percentage of participants with a complete response (CR) or partial response (PR). Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 37.5 Percentage of responders |
| XELOX/XELOX+P/XELOX+BV | BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 37.5 Percentage of responders |
Comparison: Superiority of adding bevacizumab to chemotherapy was tested as follows - H0: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX 4+P/XELOX+P) \</= 1.0 versus H1: OR(FOLFOX-4+BV/XELOX+BV)/(FOLFOX-4+P/XELOX+P) \> 1.0. The test used a two-sided significance level of 2.5%p-value: 0.988797.5% CI: [0.78, 1.28]Chi-squared
Secondary
Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
For complete responders, the duration of complete response was measured from the time measurement criteria were first met for complete response until the date that progressive disease (or death) was documented. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | 347.0 days |
| XELOX/XELOX+P/XELOX+BV | Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | 589.0 days |
Comparison: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).97.5% CI: [0.09, 1.39]
Secondary
Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
For complete responders, the duration of complete response was measured from the time measurement criteria were first met for complete response until the date that progressive disease (or death) was documented. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 403.0 days |
| XELOX/XELOX+P/XELOX+BV | Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 386.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: 0.820797.5% CI: [0.2, 7.05]Log Rank
Secondary
Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Duration of overall response was measured from the time that measurement criteria were first met for CR or PR (whichever status was recorded first) until the first date when progressive disease or death was documented. It was based on tumor assessments made by the investigators according to the RECIST criteria. Participants who neither progressed nor died were censored at the date of the last tumor assessment. Participants undergoing surgical resection with curative intent were censored at the date of surgery. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | 239.0 days |
| XELOX/XELOX+P/XELOX+BV | Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | 226.0 days |
Comparison: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV)97.5% CI: [0.86, 1.22]
Secondary
Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone
Duration of overall response was measured from the time that measurement criteria were first met for CR or PR (whichever status was recorded first) until the first date when progressive disease or death was documented. It was based on tumor assessments made by the investigators according to the RECIST criteria. Participants who neither progressed nor died were censored at the date of the last tumor assessment. Participants undergoing surgical resection with curative intent were censored at the date of surgery. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone | 225.0 days |
| XELOX/XELOX+P/XELOX+BV | Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone | 257.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: 0.030797.5% CI: [0.66, 1.01]Log Rank
Secondary
Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4
Overall survival was defined as the time from the date of randomization to the date of death. Participants who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4 | 549.0 days |
| XELOX/XELOX+P/XELOX+BV | Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4 | 577.0 days |
Comparison: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).97.5% CI: [0.84, 1.14]
Secondary
Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Overall survival was defined as the time from the date of randomization to the date of death. Participants who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 574.0 days |
| XELOX/XELOX+P/XELOX+BV | Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 551.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented together with the 97.5% confidence interval.p-value: 0.192197.5% CI: [0.72, 1.09]Log Rank
Secondary
PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4
PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the IRC. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4 | 304.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4 | 261.0 days |
Comparison: Equivalence of treatment arm A ('XELOX') to treatment arm B ('FOLFOX-4') was tested via the following hypotheses - H0: HRA/B \>/= 1.23 versus H1: HRA/B \< 1.23. HRA/B denotes the hazard of disease progression or death under treatment A ('XELOX') divided by the hazard of disease progression or death under treatment B ('FOLFOX-4').97.5% CI: [1.05, 1.42]
Secondary
PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participants who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the IRC. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the bevacizumab-containing arms was compared with the placebo-containing arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 259.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 335.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: <0.000197.5% CI: [0.58, 0.83]Log Rank
Secondary
PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4
PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants who underwent curative surgery after experiencing a sufficient shrinkage of their tumor were not censored at the date of surgery, but any relapse, new occurrence of colorectal cancer, or death was considered as an event. Non-inferiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4 | 260.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4 | 244.0 days |
Comparison: Equivalence of treatment arm A ('XELOX') to treatment arm B ('FOLFOX-4') was tested via the following hypotheses - H0: HRA/B \>/= 1.23 versus H1: HRA/B \< 1.23. HRA/B denotes the hazard of disease progression or death under treatment A ('XELOX') divided by the hazard of disease progression or death under treatment B ('FOLFOX-4').97.5% CI: [0.92, 1.15]
Secondary
PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Participants who underwent curative surgery after experiencing a sufficient shrinkage of their tumor were not censored at the date of surgery, but any relapse, new occurrence of colorectal cancer, or death was considered as an event. Superiority analysis that followed the general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 245.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 287.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: 0.001597.5% CI: [0.72, 0.95]Log Rank
Secondary
PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4
PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. The on-treatment analysis included only tumor assessments and death events that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase. Participants who did not have an event during this interval were censored at the date of the last tumor assessment within this time window, or on day 1 if no tumor assessment was available after baseline. Participants who underwent surgical resection with curative intent without prior progression within 28 days after the last confirmed intake of any study medication in the primary study treatment phase were censored at the date of surgery. The on-treatment approach excluded the possible impact of other treatments that might have been started before disease progression. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4 | 268.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4 | 234.0 days |
Comparison: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).97.5% CI: [1.07, 1.44]
Secondary
PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. The on-treatment analysis included only tumor assessments and death events that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase. Participants who did not have an event during this interval were censored at the date of the last tumor assessment within this time window, or on day 1 if no tumor assessment was available after baseline. Participants who underwent surgical resection with curative intent without prior progression within 28 days after the last confirmed intake of any study medication in the primary study treatment phase were censored at the date of surgery. The on-treatment approach excluded the possible impact of other treatments that might have been started before disease progression. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: Baseline until disease progression or death, approximately 2 years 6 months
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 241.0 days |
| XELOX/XELOX+P/XELOX+BV | PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | 316.0 days |
Comparison: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: <0.000197.5% CI: [0.52, 0.75]Log Rank
Secondary
Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
For participants whose BOR was CR or PR, time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status was recorded first) was met. It was based on tumor assessments made by the investigators according to the RECIST criteria. Results were reported as the number of participants achieving a response in 8 time categories from Week 1 to Week 54. Non-inferiority of the XELOX-containing arms was compared with the FOLFOX-4-containing arms.
Time frame: Week 1 to Week 54
Population: The EPP excluded participants from the ITT who had violated major protocol inclusion or exclusion criteria or participants who were randomized and did not receive at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 7-12 | 190 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 19-24 | 25 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 1-6 | 67 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 25-30 | 14 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 13-18 | 155 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 31-36 | 7 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 49-54 | 2 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 37-42 | 3 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 49-54 | 0 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 37-42 | 1 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 31-36 | 3 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 1-6 | 93 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 7-12 | 191 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 13-18 | 110 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 19-24 | 38 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | Week 25-30 | 13 Participants |
Secondary
Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
For participants whose BOR was CR or PR, time to response was measured as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status was recorded first) was met. It was based on tumor assessments made by the investigators according to the RECIST criteria. Results were reported as the number of participants achieving a response in 8 time categories from Week 1 to Week 54. Superiority of the BV-containing arms was compared with the chemotherapy alone arms.
Time frame: Week 1 to Week 54
Population: The ITT population included all randomized participants who provided written informed consent.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 13-18 | 105 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 25-30 | 7 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 7-12 | 146 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 31-36 | 2 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 37-42 | 1 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 19-24 | 26 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 49-54 | 0 Participants |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 1-6 | 58 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 49-54 | 1 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 1-6 | 48 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 7-12 | 138 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 31-36 | 8 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 13-18 | 87 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 19-24 | 29 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 25-30 | 12 Participants |
| XELOX/XELOX+P/XELOX+BV | Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | Week 37-42 | 2 Participants |
Secondary
Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, participant refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurred first. The general approach included all tumor assessments or deaths that occurred during the primary study treatment phase, the post-study treatment phase, or the follow-up phase. The on-treatment approach included only tumor assessments and deaths that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase only.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The safety population included all participants who were randomized and received at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | General Approach | 183.0 days |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | On-treatment Approach | 182.0 days |
| XELOX/XELOX+P/XELOX+BV | Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | General Approach | 209.0 days |
| XELOX/XELOX+P/XELOX+BV | Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone | On-treatment Approach | 208.0 days |
Comparison: General approach: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: 0.00397.5% CI: [0.74, 0.96]Log Rank
Comparison: On treatment approach: Testing for superiority was based on the stratified log-rank test and used a two-sided significance level of 2.5%.The hazard ratio (HR) of bevacizumab in combination with chemotherapy versus chemotherapy alone \[HR(FOLFOX-4+P/XELOX+P)/(FOLFOX-4+BV/XELOX+BV)\] was presented.p-value: 0.000497.5% CI: [0.7, 0.92]Log Rank
Secondary
Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, participant refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurred first. The general approach took into account all tumor assessments obtained during the primary study treatment phase, the post-study treatment phase and those obtained during the follow-up phase.The on-treatment approach included only tumor assessments and deaths that occurred no later than 28 days after the last confirmed intake of any study medication in the primary study treatment phase only.
Time frame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Population: The safety population included all participants who were randomized and received at least one dose of capecitabine, 5-FU, oxaliplatin, or bevacizumab/placebo.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | General Approach | 191.0 days |
| FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV | Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | On-treatment Approach | 190.0 days |
| XELOX/XELOX+P/XELOX+BV | Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | General Approach | 179.0 days |
| XELOX/XELOX+P/XELOX+BV | Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4 | On-treatment Approach | 176.0 days |
Comparison: General approach: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV)97.5% CI: [0.97, 1.2]
Comparison: On-treatment Approach: HRs and 97.5% confidence interval were reported for treatment arm A (XELOX/XELOX+P/XELOX+BV) versus treatment arm B (FOLFOX-4/FOLFOX-4+P/FOLFOX-4+BV).97.5% CI: [0.98, 1.23]