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

This study has been completed.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00112918
First received: June 2, 2005
Last updated: June 19, 2013
Last verified: June 2013
Results First Received: June 1, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Colorectal Cancer
Interventions: Biological: Bevacizumab
Drug: Capecitabine
Drug: 5-Fluorouracil (5-FU)
Drug: Leucovorin calcium
Drug: Oxaliplatin

  Participant Flow
  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
No text entered.

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

Reporting Groups
  Description
FOLFOX4

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

Weeks 25-48: Observation only.

FOLFOX4 + Bv

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

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

XELOX+Bv

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

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


Participant Flow:   Overall Study
    FOLFOX4   FOLFOX4 + Bv   XELOX+Bv
STARTED   1151   1155   1145 
Received Treatment   1126   1145 [1]   1135 
Stage III Disease Population   955   960   952 
COMPLETED   854 [2]   810 [2]   846 [2] 
NOT COMPLETED   297   345   299 
[1] Includes two patients from FOLFOX4 who received Bv and were assigned to FOLFOX4+Bv safety analysis
[2] Represents patients alive in follow-up at the time of final data cut-off (30 June 2012)



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

Reporting Groups
  Description
FOLFOX4

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

Weeks 25-48: Observation only.

FOLFOX4 + Bv

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

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

XELOX+Bv

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

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

Total Total of all reporting groups

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


  Outcome Measures
  Show All Outcome Measures

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

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

3.  Secondary:   Overall Survival in Stage III Cancer Patients - Time to Event   [ Time Frame: From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). ]
  Hide Outcome Measure 3

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

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

Reporting Groups
  Description
FOLFOX4

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

Weeks 25-48: Observation only.

FOLFOX4 + Bv

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

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

XELOX+Bv

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

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


Measured Values
   FOLFOX4   FOLFOX4 + Bv   XELOX+Bv 
Participants Analyzed 
[Units: Participants]
 955   960   952 
Overall Survival in Stage III Cancer Patients - Time to Event 
[Units: Months]
Median (95% Confidence Interval)
 NA [1]   NA [1]   NA [1] 
[1] Median time to event and 95% confidence intervals could not be estimated due to the low number of events.

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



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

5.  Secondary:   Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis   [ Time Frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). ]

6.  Secondary:   Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis   [ Time Frame: From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). ]


  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

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

Frequency Threshold
Threshold above which other adverse events are reported   5  

Reporting Groups
  Description
FOLFOX4

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

Weeks 25-48: Observation only.

FOLFOX4 + Bv

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

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

XELOX+Bv

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

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


Other Adverse Events
    FOLFOX4   FOLFOX4 + Bv   XELOX+Bv
Total, other (not including serious) adverse events       
# participants affected / at risk   1112/1126 (98.76%)   1127/1145 (98.43%)   1117/1135 (98.41%) 
Blood and lymphatic system disorders       
Neutropenia † 1       
# participants affected / at risk   660/1126 (58.61%)   567/1145 (49.52%)   273/1135 (24.05%) 
Thrombocytopenia † 1       
# participants affected / at risk   331/1126 (29.40%)   115/1145 (10.04%)   99/1135 (8.72%) 
Anaemia † 1       
# participants affected / at risk   116/1126 (10.30%)   89/1145 (7.77%)   74/1135 (6.52%) 
Leukopenia † 1       
# participants affected / at risk   79/1126 (7.02%)   55/1145 (4.80%)   34/1135 (3.00%) 
Eye disorders       
Lacrimation increased † 1       
# participants affected / at risk   70/1126 (6.22%)   69/1145 (6.03%)   35/1135 (3.08%) 
Gastrointestinal disorders       
Nausea † 1       
# participants affected / at risk   725/1126 (64.39%)   761/1145 (66.46%)   720/1135 (63.44%) 
Diarrhoea † 1       
# participants affected / at risk   620/1126 (55.06%)   699/1145 (61.05%)   699/1135 (61.59%) 
Vomiting † 1       
# participants affected / at risk   385/1126 (34.19%)   394/1145 (34.41%)   460/1135 (40.53%) 
Stomatitis † 1       
# participants affected / at risk   310/1126 (27.53%)   360/1145 (31.44%)   246/1135 (21.67%) 
Constipation † 1       
# participants affected / at risk   308/1126 (27.35%)   324/1145 (28.30%)   219/1135 (19.30%) 
Abdominal pain † 1       
# participants affected / at risk   220/1126 (19.54%)   227/1145 (19.83%)   214/1135 (18.85%) 
Dyspepsia † 1       
# participants affected / at risk   126/1126 (11.19%)   162/1145 (14.15%)   84/1135 (7.40%) 
Abdominal pain upper † 1       
# participants affected / at risk   86/1126 (7.64%)   118/1145 (10.31%)   113/1135 (9.96%) 
Haemorrhoids † 1       
# participants affected / at risk   29/1126 (2.58%)   68/1145 (5.94%)   41/1135 (3.61%) 
General disorders       
Fatigue † 1       
# participants affected / at risk   404/1126 (35.88%)   425/1145 (37.12%)   355/1135 (31.28%) 
Asthenia † 1       
# participants affected / at risk   241/1126 (21.40%)   251/1145 (21.92%)   250/1135 (22.03%) 
Pyrexia † 1       
# participants affected / at risk   186/1126 (16.52%)   185/1145 (16.16%)   106/1135 (9.34%) 
Mucosal inflammation † 1       
# participants affected / at risk   85/1126 (7.55%)   85/1145 (7.42%)   57/1135 (5.02%) 
Temperature intolerance † 1       
# participants affected / at risk   61/1126 (5.42%)   61/1145 (5.33%)   50/1135 (4.41%) 
Oedema peripheral † 1       
# participants affected / at risk   54/1126 (4.80%)   62/1145 (5.41%)   45/1135 (3.96%) 
Immune system disorders       
Drug hypersensitivity † 1       
# participants affected / at risk   66/1126 (5.86%)   72/1145 (6.29%)   32/1135 (2.82%) 
Infections and infestations       
Nasopharyngitis † 1       
# participants affected / at risk   76/1126 (6.75%)   92/1145 (8.03%)   70/1135 (6.17%) 
Upper respiratory tract infection † 1       
# participants affected / at risk   52/1126 (4.62%)   87/1145 (7.60%)   55/1135 (4.85%) 
Investigations       
Weight increased † 1       
# participants affected / at risk   58/1126 (5.15%)   81/1145 (7.07%)   68/1135 (5.99%) 
Weight decreased † 1       
# participants affected / at risk   26/1126 (2.31%)   56/1145 (4.89%)   61/1135 (5.37%) 
Metabolism and nutrition disorders       
Decreased appetite † 1       
# participants affected / at risk   268/1126 (23.80%)   324/1145 (28.30%)   295/1135 (25.99%) 
Musculoskeletal and connective tissue disorders       
Arthralgia † 1       
# participants affected / at risk   63/1126 (5.60%)   140/1145 (12.23%)   122/1135 (10.75%) 
Pain in extremity † 1       
# participants affected / at risk   63/1126 (5.60%)   78/1145 (6.81%)   116/1135 (10.22%) 
Back pain † 1       
# participants affected / at risk   79/1126 (7.02%)   87/1145 (7.60%)   66/1135 (5.81%) 
Musculoskeletal pain † 1       
# participants affected / at risk   35/1126 (3.11%)   86/1145 (7.51%)   46/1135 (4.05%) 
Myalgia † 1       
# participants affected / at risk   39/1126 (3.46%)   70/1145 (6.11%)   56/1135 (4.93%) 
Nervous system disorders       
Peripheral sensory neuropathy † 1       
# participants affected / at risk   430/1126 (38.19%)   430/1145 (37.55%)   436/1135 (38.41%) 
Paraesthesia † 1       
# participants affected / at risk   310/1126 (27.53%)   328/1145 (28.65%)   314/1135 (27.67%) 
Neuropathy peripheral † 1       
# participants affected / at risk   252/1126 (22.38%)   234/1145 (20.44%)   204/1135 (17.97%) 
Headache † 1       
# participants affected / at risk   169/1126 (15.01%)   284/1145 (24.80%)   219/1135 (19.30%) 
Dysgeusia † 1       
# participants affected / at risk   237/1126 (21.05%)   222/1145 (19.39%)   152/1135 (13.39%) 
Dysaesthesia † 1       
# participants affected / at risk   128/1126 (11.37%)   106/1145 (9.26%)   128/1135 (11.28%) 
Dizziness † 1       
# participants affected / at risk   102/1126 (9.06%)   117/1145 (10.22%)   79/1135 (6.96%) 
Neurotoxicity † 1       
# participants affected / at risk   60/1126 (5.33%)   69/1145 (6.03%)   50/1135 (4.41%) 
Lethargy † 1       
# participants affected / at risk   44/1126 (3.91%)   50/1145 (4.37%)   59/1135 (5.20%) 
Psychiatric disorders       
Insomnia † 1       
# participants affected / at risk   135/1126 (11.99%)   132/1145 (11.53%)   91/1135 (8.02%) 
Anxiety † 1       
# participants affected / at risk   45/1126 (4.00%)   60/1145 (5.24%)   61/1135 (5.37%) 
Renal and urinary disorders       
Proteinuria † 1       
# participants affected / at risk   19/1126 (1.69%)   73/1145 (6.38%)   69/1135 (6.08%) 
Respiratory, thoracic and mediastinal disorders       
Epistaxis † 1       
# participants affected / at risk   228/1126 (20.25%)   424/1145 (37.03%)   216/1135 (19.03%) 
Cough † 1       
# participants affected / at risk   86/1126 (7.64%)   120/1145 (10.48%)   41/1135 (3.61%) 
Dyspnoea † 1       
# participants affected / at risk   57/1126 (5.06%)   74/1145 (6.46%)   73/1135 (6.43%) 
Dysphonia † 1       
# participants affected / at risk   17/1126 (1.51%)   91/1145 (7.95%)   74/1135 (6.52%) 
Dysaesthesia pharynx † 1       
# participants affected / at risk   37/1126 (3.29%)   28/1145 (2.45%)   79/1135 (6.96%) 
Oropharyngeal pain † 1       
# participants affected / at risk   52/1126 (4.62%)   59/1145 (5.15%)   33/1135 (2.91%) 
Skin and subcutaneous tissue disorders       
Palmar-Plantar Erythrodysaesthesia Syndrome † 1       
# participants affected / at risk   98/1126 (8.70%)   119/1145 (10.39%)   435/1135 (38.33%) 
Alopecia † 1       
# participants affected / at risk   231/1126 (20.52%)   241/1145 (21.05%)   73/1135 (6.43%) 
Rash † 1       
# participants affected / at risk   114/1126 (10.12%)   112/1145 (9.78%)   110/1135 (9.69%) 
Dry skin † 1       
# participants affected / at risk   52/1126 (4.62%)   66/1145 (5.76%)   50/1135 (4.41%) 
Pruritus † 1       
# participants affected / at risk   36/1126 (3.20%)   65/1145 (5.68%)   28/1135 (2.47%) 
Vascular disorders       
Hypertension † 1       
# participants affected / at risk   196/1126 (17.41%)   472/1145 (41.22%)   468/1135 (41.23%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (13.0)



  Limitations and Caveats
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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.


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