Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

A Study of Capecitabine (Xeloda) and Bevacizumab as a First-line Therapy in Patients With Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00069095
First received: September 15, 2003
Last updated: December 11, 2015
Last verified: December 2015
Results First Received: December 11, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Colorectal Cancer
Interventions: Drug: Oxaliplatin 130 mg/m^2
Drug: Capecitabine 1000 mg/m^2
Drug: Bevacizumab 7.5 mg/kg
Drug: Placebo for bevacizumab 7.5 mg/kg
Drug: Oxaliplatin 85 mg/m^2
Drug: Leucovorin 200 mg/m^2
Drug: Fluorouracil 400 mg/m^2
Drug: Bevacizumab 5 mg/kg
Drug: Placebo for bevacizumab 5 mg/kg

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
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.
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.
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.
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.
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.
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.

Participant Flow for 3 periods

Period 1:   Primary Treatment Phase
    Xelox     Folfox-4     Xelox+P     Folfox-4+P     Xelox+BV     Folfox-4+BV  
STARTED     317     317     350     351     350     349  
COMPLETED     22     15     36     31     48     48  
NOT COMPLETED     295     302     314     320     302     301  
Ongoing                 0                 0                 5                 7                 7                 4  
Admin/Other                 29                 38                 31                 45                 48                 42  
Adverse Event                 99                 92                 71                 72                 109                 101  
Death                 14                 8                 2                 5                 8                 8  
Failure to return                 5                 5                 0                 0                 0                 2  
Insufficient Therapeutic Response                 131                 127                 175                 154                 101                 102  
Refused treatment                 15                 26                 17                 31                 24                 27  
Withdrew                 2                 3                 8                 2                 4                 9  
Other Violation                 0                 1                 1                 1                 0                 1  
Violation criteria                 0                 2                 4                 3                 1                 5  

Period 2:   Post-study Treatment Phase
    Xelox     Folfox-4     Xelox+P     Folfox-4+P     Xelox+BV     Folfox-4+BV  
STARTED     8 [1]   13 [1]   21 [1]   17 [1]   36 [1]   29 [1]
COMPLETED     0     0     0     0     0     0  
NOT COMPLETED     8     13     21     17     36     29  
Missing reason                 1                 3                 12                 8                 18                 17  
Adverse Event                 2                 3                 1                 0                 5                 1  
Eligible for surgery                 2                 0                 0                 0                 0                 0  
Insufficient therapeutic response                 1                 4                 5                 6                 7                 9  
Participant refusal/Admin reasons                 1                 0                 0                 0                 0                 1  
Participant had complete response                 1                 1                 0                 0                 0                 0  
More than 21 days delay between cycles                 0                 1                 0                 0                 0                 0  
Investigator decision (enough treatment)                 0                 1                 1                 0                 1                 0  
Participant withdrew consent                 0                 0                 1                 0                 0                 0  
Participant will start new treatment                 0                 0                 1                 0                 0                 0  
Participant wanted break from treatment                 0                 0                 0                 1                 0                 0  
Participant completed treatment                 0                 0                 0                 1                 0                 0  
Surgery                 0                 0                 0                 1                 1                 0  
Death                 0                 0                 0                 0                 1                 0  
Participant had progressive disease                 0                 0                 0                 0                 1                 0  
Participant/Physician decision to stop                 0                 0                 0                 0                 1                 0  
Preplanned 6 cycles after surgery                 0                 0                 0                 0                 1                 0  
Investigator decision                 0                 0                 0                 0                 0                 1  
[1] Participants could enter the follow-up phase even without entering the post-study treatment phase.

Period 3:   Follow-up Phase
    Xelox     Folfox-4     Xelox+P     Folfox-4+P     Xelox+BV     Folfox-4+BV  
STARTED     284 [1]   299 [1]   298 [1]   299 [1]   278 [1]   272 [1]
COMPLETED     110     93     178     187     186     171  
NOT COMPLETED     174     206     120     112     92     101  
Death                 174                 206                 120                 112                 92                 101  
[1] Participants could enter the follow-up phase even without entering the post-study treatment phase.



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Baseline characteristics were described for the Intent-to-treat (ITT) population.This population included all randomized participants who provided written informed consent.

Reporting Groups
  Description
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.
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.
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.
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.
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.
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.
Total Total of all reporting groups

Baseline Measures
    Xelox     Folfox-4     Xelox+P     Folfox-4+P     Xelox+BV     Folfox-4+BV     Total  
Number of Participants  
[units: participants]
  317     317     350     351     350     349     2034  
Age  
[units: years]
Mean (Standard Deviation)
  60.3  (10.76)     60.6  (10.94)     59.1  (12.14)     58.8  (10.87)     59.7  (11.28)     59.7  (10.74)     59.7  (11.14)  
Gender  
[units: participants]
             
Female     123     113     145     165     137     144     827  
Male     194     204     205     186     213     205     1207  



  Outcome Measures
  Show All Outcome Measures

1.  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   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

2.  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   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

3.  Secondary:   PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

4.  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   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

5.  Secondary:   PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

6.  Secondary:   PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

7.  Secondary:   PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

8.  Secondary:   PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

9.  Secondary:   Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

10.  Secondary:   Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: Baseline until disease progression or death, approximately 2 years 6 months ]

11.  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   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

12.  Secondary:   Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

13.  Secondary:   BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

14.  Secondary:   BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

15.  Secondary:   Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

16.  Secondary:   Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

17.  Secondary:   Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: Week 1 to Week 54 ]

18.  Secondary:   Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: Week 1 to Week 54 ]

19.  Secondary:   Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

20.  Secondary:   Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

21.  Secondary:   Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]

22.  Secondary:   Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone   [ Time Frame: From baseline until disease progression/recurrence, approximately 2 years 6 months ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
  Hide More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Roche Trial Information Hotline
Organization: F. Hoffmann-La Roche AG
phone: +41 61 6878333
e-mail: global.trial_information@roche.com



Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00069095     History of Changes
Other Study ID Numbers: NO16966
Study First Received: September 15, 2003
Results First Received: December 11, 2015
Last Updated: December 11, 2015
Health Authority: United States: Food and Drug Administration