A Study of Avastin (Bevacizumab) in Combination Chemotherapy in Patients With Metastatic Cancer of the Colon or Rectum

Study Overview
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Brief Summary
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A study of Avastin (bevacizumab) in combination chemotherapy in patients with metastatic cancer of the colon or rectum. The anticipated time on study treatment is until disease progression.

Official Title
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A Randomized, Open-label Study Comparing the Effect of 3 Chemotherapy Regimens Containing Avastin on Time to Disease Progression in Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Bevacizumab [Avastin]
* Drug: Capecitabine
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients >=18 years of age; colon or rectal cancer, with metastases; >=1 measurable lesion. Exclusion Criteria: previous systemic treatment for advanced disease; radiotherapy to any site within 4 weeks before study; daily aspirin (>325 mg/day), anticoagulants, or other medications known to predispose to gastrointestinal ulceration; co-existing malignancies or malignancies diagnosed within last 5 years (except basal cell cancer or cervical cancer in situ).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2)<br>Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. | Drug: Bevacizumab [Avastin]<br>* Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle.<br>* Other names: Avastin;Drug: Capecitabine<br>* Capecitabine was administered orally at a doses of 1000 or 1250, mg/m^2 twice daily (Day 2 to 15) or as 650 mg/m^2 twice daily on Days 1 to 21.<br>Drug: Irinotecan<br>* Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks.<br>|
| Experimental: Bevacizumab + Capecitabine (1250 mg/m^2)<br>Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. | Drug: Bevacizumab [Avastin]<br>* Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle.<br>* Other names: Avastin;Drug: Capecitabine<br>* Capecitabine was administered orally at a doses of 1000 or 1250, mg/m^2 twice daily (Day 2 to 15) or as 650 mg/m^2 twice daily on Days 1 to 21.<br>|
| Experimental: Bevacizumab + Capecitabine (650 mg/m^2)<br>Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 Week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of capecitabine treatment without interruptions. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal. | Drug: Bevacizumab [Avastin]<br>* Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle.<br>* Other names: Avastin;Drug: Capecitabine<br>* Capecitabine was administered orally at a doses of 1000 or 1250, mg/m^2 twice daily (Day 2 to 15) or as 650 mg/m^2 twice daily on Days 1 to 21.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease Progression or Death | Disease progression was defined according to National Cancer Institute (NCI) guidelines and best clinical practices. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Time to Progression (TTP) | TTP is defined as the time from date of randomization until objective tumor progression or death due to any cause. It includes deaths and thus can be correlated to overall survival. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died | Overall survival is defined as the time from date of randomization until death from any cause | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Overall Survival | Overall survival is defined as the time from date of randomization until death from any cause; Kaplan-Meier estimates were used for analysis. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants With Treatment Failure | Treatment failure is defined as discontinuation of treatment for any reason, including disease progression, death, treatment toxicity, insufficient therapeutic response, failure to return, refusing treatment, being unwilling to cooperate and withdrawing consent. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Time to Treatment Failure | Time to treatment failure is defined as a composite endpoint measuring time from date of randomization to discontinuation of treatment for any reason, including disease progression, death, treatment toxicity, insufficient therapeutic response, failure to return, refusing treatment, being unwilling to cooperate and withdrawing consent. Analysis was performed using Kaplan-Meier estimates. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants With Progression Excluding Deaths | The failure event was defined as tumor progression excluding deaths due to any reason. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Time to Progression Excluding Deaths | The failure event was defined as tumor progression excluding deaths due to any reason. Kaplan-Meier estimates were used for analysis. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants With Progression Excluding Deaths Not Related to Underlying Cancer | The failure event was defined as tumor progression excluding only deaths not related to underlying cancer. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Time to Progression Excluding Deaths Not Related to Underlying Cancer | The failure event was defined as tumor progression excluding only deaths not related to underlying cancer. Kaplan-Meier estimates were used for analysis. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants by Best Overall Response | Best overall response is defined as the best response recorded from the date of randomization until disease progression or recurrence. Complete response (CR): at least 2 determinations of CR at least 4 weeks apart before progression; Partial response (PR): at least 2 determinations of PR at least 4 weeks apart before progression; Stable disease (SD): at least one SD assessment; Progressive Disease (PD): Disease progression or death due to underlying cancer. CR: Complete disappearance of all target lesions; PR: At least 30% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of all target lesions; PD: At least 20% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of longest diameter of all target lesions or the appearance of one or more new lesions; SD: Neither sufficient shrinkage to qualify for CR or PR or increase in lesions; | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants With a Best Overall Response of CR or PR | CR: Complete disappearance of all target lesions; PR: At least 30% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of all target lesions; | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants With Stable Disease | Stable disease rate was the proportion of participants who achieved CR, PR, or SD. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Percentage of Participants With Progressive Disease Within 12 Weeks From Start of Treatment | Early progression was the proportion of participants with progressive disease within 12 weeks from the start of treatment. | Randomization, Weeks 3, 6 and 9, and 12 | 
| Duration of Overall Response | Duration of overall response included participants who achieved a CR or PR. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Duration of Stable Disease (SD) | Duration of SD was calculated as the number of months the participants remained in CR, PR or SD. Kaplan-Meier estimates were used for analysis. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death | 
| Duration of Overall Complete Response | Duration of complete response was calculated as the time in months from the date of randomization to the date of first documentation of CR. Kaplan-Meier estimates were used for analysis. | Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years |