A Study of Xeloda (Capecitabine) Plus Oxaliplatin in Patients With Colon Cancer

Study Overview
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Brief Summary
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This 2 arm study will compare the efficacy and safety of intermittent oral Xeloda plus Eloxatin (oxaliplatin) with that of fluorouracil/leucovorin in patients who have had surgery for colon cancer and no previous chemotherapy. Patients will be randomized to receive either 1) XELOX (Xeloda 1000mg/m2 po bid on days 1-15 + oxaliplatin) in 3 week cycles or 2)5-fluorouracil + leucovorin in 4 or 8 week cycles. The anticipated time on study treatment is until disease progression and the target sample size is 500+ individuals.

Official Title
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An Open-Label Randomized Phase III Study of Intermittent Oral Capecitabine in Combination With Intravenous Oxaliplatin (Q3W) (XELOX) Versus Fluorouracil/Leucovorin as Adjuvant Therapy for Patients Who Have Undergone Surgery for Colon Carcinoma, AJCC/UICC Stage III (Dukes Stage C)

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Oxaliplatin
* Drug: Leucovorin (LV)
* Drug: 5-Fluorouracil (5-FU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed colon carcinoma, AJCC/UICC Stage III (Dukes stage C) Complete tumor resection; Patients operated with curative intent and with no macroscopic or microscopic evidence for remaining tumor who can be randomized to either treatment arm within 8 weeks after surgery. As this is an adjuvant trial patients should never have had any evidence of metastatic disease (including presence of tumor cells in the ascites). Have a life expectancy of at least 5 years Exclusion Criteria: Pregnant or lactating women Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study Previous cytotoxic chemotherapy, radiotherapy or immunotherapy, for the currently treated colon cancer Patients who have not completely recovered from surgery

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 |
| --- | --- |
| Active Comparator: 5-Fluorouracil/Leucovorin (5-FU/LV)<br>Participants were given one of two regimens (each participating center prespecified which regimen they would use for all patients at that center): i) Mayo Clinic regimen group: LV 20 mg/m^2 IV bolus injection + 5-FU 425 mg/m^2 IV bolus injection daily on Days 1-5 of a four-week cycle, for a total of six cycles (24 weeks), or; ii) Roswell Park regimen group: LV 500 mg/m^2 by two-hour IV infusion + 5-FU 500 mg/m^2 IV bolus injection one hour after the start of the LV infusion on Day 1 of Weeks 1 to 6 of each eight-week cycle, for a total of four cycles (32 weeks). | Drug: Leucovorin (LV)<br>* Administered by one of two regimens, as specified in the arm description.<br>Drug: 5-Fluorouracil (5-FU)<br>* Administered by one of two regimens, as specified in the arm description.<br>|
| Experimental: Capecitabine in Combination with Oxaliplatin (XELOX)<br>Capecitabine was administered as an oral twice daily outpatient intermittent treatment (3-week cycles consisting of two weeks of treatment followed by one week without treatment) combined with intravenous (IV) oxaliplatin on Day 1 of each cycle. Capecitabine 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 the first dose given during the evening of Day 1 and last dose given during the morning of Day 15. Oxaliplatin was administered as a 130 mg/m^2 IV infusion over two hours on Day 1 of each cycle. The XELOX combination was administered for a total of eight cycles (24 weeks). | Drug: Capecitabine<br>* 1000 milligrams per square metre of body surface area (mg/m^2) orally twice daily on days 1-15 of each 3-week cycle.<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* 130 mg/m^2 intravenous (IV) infusion over two hours on Day 1 of each 3-week cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) [Number of Events] | Determination of an event was based on tumor assessments and survival follow-up assessments. A disease-free survival (DFS) event was defined as any recurrence of the original colon cancer or appearance of a new colon or rectal cancer (proven by cytology or histology, when possible) or death due to any cause, whichever was earliest. Participants who had not had any such event at the time of data analysis were censored at the last date they were known to be event-free. Participants with no tumor assessments after baseline were censored at Day 1. An isolated event of increased CEA, or unexplained clinical deterioration were not considered to be evidence of relapse without support of other objective measurements. The date of relapse was defined as the date of the definitive assessment by objective measurements. | Time from randomization date to date of first DFS event/date last known to be event-free. Median observation time for DFS was 74 months (range: 0-95 months). | 
| Disease-Free Survival (DFS) [Time to Event] | Determination of an event was based on tumor assessments and survival follow-up assessments. A disease-free survival (DFS) event was defined as any recurrence of the original colon cancer or appearance of a new colon or rectal cancer (proven by cytology or histology, when possible) or death due to any cause, whichever was earliest. Participants who had not had any such event at the time of data analysis were censored at the last date they were known to be event-free. Participants with no tumor assessments after baseline were censored at Day 1. An isolated event of increased CEA, or unexplained clinical deterioration were not considered to be evidence of relapse without support of other objective measurements. The date of relapse was defined as the date of the definitive assessment by objective measurements. The median was estimated by the Kaplan-Meier method. The full range values include censored observations. | Time from randomization date to date of first DFS event/date last known to be event-free. Median observation time for DFS was 74 months (range: 0-95 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-Free Survival (RFS) [Number of Events] | A relapse-free survival (RFS) event included recurrence of the original colon cancer, development of a new colon or rectal cancer, and deaths related to any of the following: treatment, recurrence of the original colon cancer, or development of a new colon or rectal cancer. Participants who had not had any such event at the time of data analysis were censored at the last date they were known to be event-free. Participants whose cause of death was unrelated to treatment or disease recurrence were censored at the time of the last tumor assessment. | Time from randomization date to date of first RFS event/date last known to be event-free. Median observation time for RFS was 74 months (range: 0-95 months). | 
| Relapse-Free Survival (RFS) [Time to Event] | A relapse-free survival (RFS) event included recurrence of the original colon cancer, development of a new colon or rectal cancer, and deaths related to any of the following: treatment, recurrence of the original colon cancer, or development of a new colon or rectal cancer. Participants who had not had any such event at the time of data analysis were censored at the last date they were known to be event-free. Participants whose cause of death was unrelated to treatment or disease recurrence were censored at the time of the last tumor assessment. The median was estimated by the Kaplan-Meier method. The full range values include censored observations. | Time from randomization date to date of first RFS event/date last known to be event-free. Median observation time for RFS was 74 months (range: 0-95 months). | 
| Overall Survival [Number of Events] | Overall survival was measured as the time from randomization to the date of death, irrespective of the cause of death. Participants who were not reported as having died at the time of the analysis were censored using the date they were last known to be alive. | Time from randomization date to date of death/date last known to be alive. Median observation time was 83 months (range: 0-95 months). | 
| Overall Survival [Time to Event] | Overall survival was measured as the time from randomization to the date of death, irrespective of the cause of death. Participants who were not reported as having died at the time of the analysis were censored using the date they were last known to be alive. The median was estimated by the Kaplan-Meier method. The full range values include censored observations. | Time from randomization date to date of death/date last known to be alive. Median observation time was 83 months (range: 0-95 months). | 
| Number of Participants With at Least One Adverse Event by Most Severe Intensity | The intensity of all adverse events (AEs) was categorized according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) (version 3.0) grading system. If an AE had occurred which was not contained in the NCI-CTC, a four-point scale (mild, moderate, severe, life-threatening) was used. The terms severe and serious are not synonymous and are independently assessed for each AE. Only the most severe intensity was counted for multiple occurrences of an AE in one individual. See the AEs results table for details. | From time of very first drug intake to 28 days after very last drug intake (median [full range] duration of study treatment per arm: 5-FU/LV MAYO CLINIC: 145 [4-208] days; 5-FU/LV ROSWELL PARK: 204 [1-239] days; XELOX: 163 [1-275] days). |