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

A 2x2 Factorial Randomized Phase III Study of Intermittent Oral Capecitabine in Combination With Intravenous Oxaliplatin (Q3W) ("XELOX") With/Without Intravenous Bevacizumab (Q3W) Versus Bolus and Continuous Infusion Fluorouracil/Intravenous Leucovorin With Intravenous Oxaliplatin (Q2W) ("FOLFOX-4") With/Without Intravenous Bevacizumab (Q2W) as First-line Treatment for Patients With Metastatic Colorectal Cancer

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).

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin 130 mg/m^2; Drug: Capecitabine 1000 mg/m^2; Drug: Placebo for bevacizumab 7.5 mg/kg; Drug: Bevacizumab 7.5 mg/kg; Drug: Oxaliplatin 85 mg/m^2; Drug: Leucovorin 200 mg/m^2; Drug: Fluorouracil 400 mg/m^2; Drug: Placebo for bevacizumab 5 mg/kg; Drug: Bevacizumab 5 mg/kg

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.

• Study Type: Interventional
• Enrollment (Actual): 2035
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5011
  • Box Hill, Australia, 3128
  • Brisbane, Australia, 4101
  • Camperdown, Australia, 2050
  • Fitzroy, Australia, 3065
  • Footscray, Australia, 3011
  • Kurralta Park, Australia, 5037
  • Malvern, Australia, 3144
  • Melbourne, Australia, 3002
  • Melbourne, Australia, 3181
  • Perth, Australia, 6000
  • Port Macquarie, Australia, 2444
  • St. Leonards, Australia, 2065
  • Sydney, Australia, 2031
  • Sydney, Australia, 2139
• Austria
  • Wels, Austria, 4600
  • Wien, Austria, 1090
• Brazil
  • JAÚ, Brazil, 17210-080
  • Rio de Janeiro, Brazil, 20231-050
  • Sao Paulo, Brazil, 05403-000
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
    • Edmonton, Alberta, Canada, T6G 1Z2
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
    • North Vancouver, British Columbia, Canada, V7L 2L7
    • Surrey, British Columbia, Canada, V3V 1Z2
    • Vancouver, British Columbia, Canada, V5Z 1H5
    • Victoria, British Columbia, Canada, V8R 6V5
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
    • London, Ontario, Canada, N6A 4L6
    • Mississauga, Ontario, Canada, L5M 2N1
    • Oshawa, Ontario, Canada, L1G 2B9
    • Ottawa, Ontario, Canada, K1H 8L6
    • St. Catharines, Ontario, Canada, L2R 7C6
    • Toronto, Ontario, Canada, M5G 2M9
    • Toronto, Ontario, Canada, M4N 3M5
    • Toronto, Ontario, Canada, M5G 1X5
    • Toronto, Ontario, Canada, M9N 1N8
  • Quebec
    • Levis, Quebec, Canada, G6V 3Z1
    • Montreal, Quebec, Canada, H1T 2M4
    • Montreal, Quebec, Canada, H4J 1C5
    • Montreal, Quebec, Canada, H2L 4M1
    • Quebec City, Quebec, Canada, G1R 2J6
• China
  • Beijing, China, 100021
  • Beijing, China, 100853
  • Guangdong, China, 510515
  • Guangzhou, China, 510060
  • Jiangsu, China, 210009
  • Jiangxi, China, 330000
  • Shandong, China, 250117
  • Shanghai, China, 200025
  • Shanghai, China, 200092
  • Tianjin, China, 300060
  • Wuhan, China, 430030
• Czech Republic
  • Brno, Czech Republic, 656 53
  • Chomutov, Czech Republic, 430 12
  • Hradec Kralove, Czech Republic, 500 36
  • Ostrava, Czech Republic, 708 52
• Denmark
  • Herlev, Denmark, 2730
  • København, Denmark, 2100
  • Odense, Denmark, 5000
• Finland
  • Helsinki, Finland, 00029
  • Tampere, Finland, 33520
  • Turku, Finland, 20520
• France
  • Besancon, France, 25030
  • Bobigny, France, 93009
  • Boulogne-billancourt, France, 92104
  • Brest, France, 29609
  • Chambray Les Tours, France, 37171
  • Colmar, France, 68024
  • Dijon, France, 21079
  • Grenoble, France, 38100
  • Lyon, France, 69373
  • Metz, France, 57072
  • Nice, France, 06202
  • Nice, France, 06189
  • Nimes, France, 30029
  • Paris, France, 75651
  • Paris, France, 75475
  • Paris, France, 75679
  • Pierre Benite, France, 69495
  • Rouen, France, 76031
  • Saint Herblain, France, 44805
  • Saint Herblain, France, 44093
  • Toulouse, France, 31052
• Germany
  • Bochum, Germany, 44892
  • Halle, Germany, 06120
  • Hannover, Germany, 30625
  • Herne, Germany, 44625
  • Leipzig, Germany, 04129
  • Mainz, Germany, 55131
  • Mannheim, Germany, 68167
  • Regensburg, Germany, 93053
  • Stralsund, Germany, 18435
  • Trier, Germany, 54290
• Guatemala
  • Guatemala, Guatemala, 01009
  • Guatemala City, Guatemala, 01015
• Hong Kong
  • Hong Kong, Hong Kong
• Hungary
  • Budapest, Hungary, 1082
  • Budapest, Hungary, H-1122
  • Gyor, Hungary, 9002
  • Kecskemet, Hungary, 6000
• Ireland
  • Cork, Ireland
  • Dublin, Ireland, 4
  • Dublin, Ireland, 8
  • Galway, Ireland
• Israel
  • Haifa, Israel, 31096
  • Jerusalem, Israel, 91120
  • Petach Tikva, Israel, 49100
  • Tel Aviv, Israel, 64239
  • Zerifin, Israel, 70300
• Italy
  • Ancona, Italy, 60121
  • Genova, Italy, 16132
  • Modena, Italy, 41100
  • Padova, Italy, 35100
  • Parma, Italy, 43100
  • Pavia, Italy, 27100
  • Reggio Emilia, Italy, 42100
  • Sassari, Italy, 07100
• Korea, Republic of
  • Seoul, Korea, Republic of, 135-170
• Mexico
  • Mexico City, Mexico, 14000
• New Zealand
  • Christchurch, New Zealand
• Norway
  • Bergen, Norway, 5021
  • Oslo, Norway, 0407
  • Tromsø, Norway, 9038
• Panama
  • Panama City, Panama
• Portugal
  • Beja, Portugal, 7801-849
  • Lisboa, Portugal, 1649-035
• Puerto Rico
  • San Juan, Puerto Rico, 00907
• Russian Federation
  • Moscow, Russian Federation, 105229
  • Moscow, Russian Federation, 115478
  • Moscow, Russian Federation, 117837
  • St Petersburg, Russian Federation, 197758
  • St Petersburg, Russian Federation, 198255
• South Africa
  • Cape Town, South Africa, 7506
  • Pretoria, South Africa, 0001
  • Sandton, South Africa, 2199
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08035
  • Córdoba, Spain, 14004
  • Granada, Spain, 18014
  • Leganes, Spain, 28911
  • Madrid, Spain, 28040
  • Madrid, Spain, 28046
  • Madrid, Spain, 28034
  • Madrid, Spain, 28041
  • Madrid, Spain, 28007
  • Málaga, Spain, 29010
  • Santander, Spain, 39008
  • Valencia, Spain, 46026
  • Valencia, Spain, 46010
  • Valencia, Spain, 46009
  • Zaragoza, Spain, 50009
• Sweden
  • Gaevle, Sweden, 80187
  • Karlstad, Sweden, 65185
  • Stockholm, Sweden, 17176
  • Uppsala, Sweden, 751 85
  • Västerås, Sweden, 72189
• Switzerland
  • Bern, Switzerland, 3010
  • Geneve, Switzerland, 1205
• Taiwan
  • Kueishan, Taiwan, 333
  • Taipei, Taiwan, 100
  • Taipei, Taiwan, 114
  • Taipei, Taiwan, 112
• Thailand
  • Bangkok, Thailand, 10700
  • Bangkok, Thailand, 10110
  • Khon Kaen, Thailand, 40002
• Turkey
  • Istanbul, Turkey, 34300
  • Izmir, Turkey, 35100
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
  • Birmingham, United Kingdom, B18 7QH
  • Cardiff, United Kingdom, CF14 2TL
  • Derby, United Kingdom, DE1 2QY
  • Glasgow, United Kingdom, G12 0YN
  • Guildford, United Kingdom, GU2 7XX
  • Hull, United Kingdom, HU8 9HE
  • London, United Kingdom, SW3 6JJ
  • Maidstone, United Kingdom, ME16 9QQ
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
  • Northwood, United Kingdom, HA6 2RN
  • Nottingham, United Kingdom, NG5 1PB
  • Plymouth, United Kingdom, PL6 8DH
  • Salisbury, United Kingdom, SP2 8BJ
  • Southampton, United Kingdom, SO9 4PE
  • Sutton, United Kingdom, SM2 5PT
  • Taunton, United Kingdom, TA1 5DA
• United States
  • California
    • Berkeley, California, United States, 94704
    • Fountain Valley, California, United States, 92708
    • Fullerton, California, United States, 92835
    • Gilroy, California, United States, 95020
    • Greenbrae, California, United States, 94904
    • Los Angeles, California, United States, 90057
    • Orange, California, United States, 92868
    • Palo Alto, California, United States, 94304
    • San Diego, California, United States, 92123
  • Connecticut
    • Norwich, Connecticut, United States, 06360
    • Waterbury, Connecticut, United States, 06708
  • Florida
    • Boca Raton, Florida, United States, 33486
    • Gainesville, Florida, United States, 33610-0277
    • Jacksonville, Florida, United States, 32207
    • New Port Richey, Florida, United States, 34652
    • Tampa, Florida, United States, 33607
    • Tampa, Florida, United States, 33647
  • Georgia
    • Atlanta, Georgia, United States, 30341
  • Illinois
    • Chicago, Illinois, United States, 60640
    • Elk Grove Village, Illinois, United States, 60007
    • Peoria, Illinois, United States, 61615-7828
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0098
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
  • Maine
    • Scarborough, Maine, United States, 04074
  • Massachusetts
    • Boston, Massachusetts, United States, 02135
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
  • Minnesota
    • St Louis Park, Minnesota, United States, 55416
  • Nevada
    • Las Vegas, Nevada, United States, 89106
  • New Jersey
    • East Orange, New Jersey, United States, 07019
    • Hamilton, New Jersey, United States, 08690
    • New Brunswick, New Jersey, United States, 08901
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-0001
    • Farmington, New Mexico, United States, 87401
  • New York
    • New York, New York, United States, 10065
    • Rochester, New York, United States, 14623
    • Syracuse, New York, United States, 13210
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
    • Charlotte, North Carolina, United States, 28233-3549
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
    • Fargo, North Dakota, United States, 58122
  • Pennsylvania
    • Sayre, Pennsylvania, United States, 18840
    • Upland, Pennsylvania, United States, 19013
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
  • South Carolina
    • Charleston, South Carolina, United States, 29425
    • Columbia, South Carolina, United States, 29209
  • Tennessee
    • Memphis, Tennessee, United States, 38120
  • Texas
    • Houston, Texas, United States, 77024
  • Vermont
    • Burlington, Vermont, United States, 05401
  • Virginia
    • Richmond, Virginia, United States, 23294

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: XELOX (oxaliplatin+capecitabine); Patients in the 2-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.	Drug: Oxaliplatin 130 mg/m^2; Oxaliplatin was administered in a 2 h infusion before the first dose of capecitabine.; Other Names: Eloxatin; Drug: Capecitabine 1000 mg/m^2; Capecitabine was taken within 30 min after the end of breakfast and dinner.; Other Names: Xeloda; Drug: Placebo 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.
EXPERIMENTAL: XELOX (oxaliplatin+capecitabine) + bevacizumab; Patients in the 4-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle + bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.	Drug: Oxaliplatin 130 mg/m^2; Oxaliplatin was administered in a 2 h infusion before the first dose of capecitabine.; Other Names: Eloxatin; Drug: Capecitabine 1000 mg/m^2; Capecitabine was taken within 30 min after the end of breakfast and dinner.; Other Names: Xeloda; Drug: Bevacizumab 7.5 mg/kg; Bevacizumab was administered in a 30 to 90 min infusion.; Other Names: Avastin
ACTIVE_COMPARATOR: FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil); Patients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + 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. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.	Drug: Oxaliplatin 85 mg/m^2; Oxaliplatin 85 mg/m^2 was administered simultaneously with leucovorin in a 2 h infusion.; Other Names: Eloxatin; Drug: Leucovorin 200 mg/m^2; Leucovorin was administered simultaneously with oxaliplatin 85 mg/m^2 in a 2 h infusion.; Drug: Fluorouracil 400 mg/m^2; Other Names: Efudex; Drug: Placebo 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.
ACTIVE_COMPARATOR: FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumab; Patients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + 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.	Drug: Oxaliplatin 85 mg/m^2; Oxaliplatin 85 mg/m^2 was administered simultaneously with leucovorin in a 2 h infusion.; Other Names: Eloxatin; Drug: Leucovorin 200 mg/m^2; Leucovorin was administered simultaneously with oxaliplatin 85 mg/m^2 in a 2 h infusion.; Drug: Fluorouracil 400 mg/m^2; Other Names: Efudex; Drug: Bevacizumab 5 mg/kg; Bevacizumab was administered in a 30 to 90 min infusion.; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	Baseline until disease progression or death, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	Week 1 to Week 54
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.	Week 1 to Week 54
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months
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.	From baseline until disease progression/recurrence, approximately 2 years 6 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (ACTUAL): January 1, 2006
• Study Completion (ACTUAL): April 1, 2009

Study Registration Dates

• First Submitted: September 15, 2003
• First Submitted That Met QC Criteria: September 17, 2003
• First Posted (ESTIMATE): September 18, 2003

Study Record Updates

• Last Update Posted (ESTIMATE): October 6, 2016
• Last Update Submitted That Met QC Criteria: August 26, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Capecitabine; Oxaliplatin; Bevacizumab; Leucovorin
• Other Study ID Numbers: NO16966