This non-randomized, open-label, outpatient clinical trial is designed to assess the safety and efficacy of daily orally administered EKB-569 in subjects with advanced colorectal cancer. Patients must have been previously treated with a fluoropyrimidine (5-FU or capecitabine) and either oxaliplatin or irinotecan (given concurrently or as separate regimens).

The primary objective of the study is to assess the clinical activity of EKB-569 administered orally as a second-line or later stage treatment in subjects with advanced colorectal cancer.

Secondary objectives include:

• To further evaluate the safety of EKB-569
• To explore additional clinical activity parameters
• To explore subject survival
• To evaluate the pharmacokinetics of EKB-569
• To assess subject reported outcomes

EKB-569 will be administered orally as a single-agent. Eligible subjects will take EKB-569 daily as long as they do not have progressive disease and are tolerating treatment.

Inclusion Criteria:

• Signed and dated, institutional review board (IRB) or independent ethics committee (IEC)-approved informed consent form before any protocol-specific screening procedures
• Previous histologic diagnosis of adenocarcinoma of the colon or rectum
• EGFR expression by immunohistochemical analysis (must be > or = 20% positive tumor cells in prior tumor biopsy specimens)

Exclusion Criteria:

• Chemotherapy, radiotherapy, anticancer immunotherapy, or investigational agents within 4 weeks of treatment day 1 (6 weeks if the previous regimen included mitomycin or nitrosoureas).
• Prior epidermal growth factor receptor-targeting therapy
• Known central nervous system (CNS) metastases