Inclusion Criteria:

• Histologically or cytologically documented locally advanced or metastatic colorectal cancer
• 1-2 prior therapies for metastatic colorectal cancer. Prior adjuvant therapy not included in the number of priors unless recurrence within 12 months of last dose of therapy and then the adjuvant therapy will be counted.
• Tumor is K-ras wildtype by method of choice at respective institution (testing codons 12 and 13)
• Measurable disease according to the RECIST criteria
• 18 years of age or older
• ECOG Performance Status of 0-2
• Completed any major surgery 4 weeks from registration and any minor surgery 2 weeks from registration
• Adequate bone marrow function
• Adequate renal function
• Adequate hepatic function
• Normal range of serum calcium and magnesium
• Agree to use an effective form of contraception during the study and 90 days following the last dose of medication
• Negative urine or serum pregnancy test

Exclusion Criteria:

• History of prior malignancy within the past 3 years except curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or treated localized prostate cancer
• Prior therapy with gefitinib, erlotinib, cetuximab, ABX-EGF or other specific EGFR inhibitor
• Known hypersensitivity to any components of each drug
• Pregnant or lactating women
• Any other medical condition, including mental illness or substance abuse, deemed by the clinician to be likely to interfere
• Potassium < 4.0 mEg/L despite supplementation
• Evidence of severe or uncontrolled systemic disease or any concurrent illness that, in the opinion of the investigator, makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
• Clinically significant cardiac event such as myocardial infarction: NYHA classification of heart disease greater than or equal to 2 that, in the opinion of the investigator, increases the risk of ventricular arrhythmia within 3 months before entry; or presence of cardiac disease
• History of arrythmia which is symptomatic or requires treatment or asymptomatic sustained ventricular tachycardia
• Previous history of QTc prolongation as a result from other medication that required discontinuation of that medication
• Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age
• Presence of left bundle branch block
• QTc with Bazett's correction that is unmeasurable , or greater then 480msec on screening ECG
• Any concomitant medication that may cause QTc prolongation, induce Torsades de Pointes or induce CYP3A4 function
• Hypertension not controlled by medical therapy
• Patients lacking physical integrity of the upper gastrointestinal tract or who have malabsorption syndrome
• Currently active diarrhea that may affect patient's ability to absorb ZD6474 or tolerate potential diarrhea from study drugs
• For patients entering dose levels 4-6, prior history of irinotecan toxicity requiring a dose reduction lower than the dose of irinotecan that the patient will be receiving on this study
• Receipt of any investigational agents within 30 days prior to commencing study treatment
• Last dose of prior chemotherapy or radiation therapy discontinued less thn 4 weeks before the start of study therapy
• Incompletely healed surgical incisions, at the discretion of the investigator
• Any unresolved toxicity greater than CTC grade 1 from previous anti-cancer therapy