• The primary objective is to compare the antitumor activity of pemetrexed plus a comparator with that of leucovorin modulated 5 FU plus a comparator as measured by tumor response rate for patients with locally advanced or metastatic colorectal cancer
  

• The secondary objectives of the study are as follows:
  
• to assess the following time to event efficacy endpoints for patients in both treatment arms:
  
• overall survival
  
• progression free survival
  
• duration of response
  
• to characterize the quantitative and qualitative toxicities of both treatment arms in this patient population
  

Inclusion Criteria:

The patient must have:

• Histologic or cytologic diagnosis of adenocarcinoma of the colon or rectum.
• Performance status of 0 to 2 on the ECOG Performance Status Scale.
• Standard postoperative adjuvant radiation therapy for rectal cancer is allowed.
• Locally advanced or metastatic disease.
• Must be 18 years of age.

Exclusion Criteria:

The patient must not have:

• Received prior chemotherapy for advanced disease. Prior adjuvant therapy, including 5-FU, is allowed if it has been more than 12 months since the last treatment.
• Received prior treatment with irinotecan in the adjuvant setting.
• Are unable to take vitamin B12 or folic acid.
• Are unable to interrupt aspirin, other nonsteroidal anti-inflammatory drugs, or COX-2 inhibitors for a 5-day period.
• Have a second primary malignancy except carcinoma in situ of the cervix or nonmelanomatous skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence.