Study of FOLFIRI Plus Cetuximab Plus IMO-2055 in Patients With Colorectal Cancer

Inclusion Criteria: Patients must satisfy all the following inclusion criteria in order to be eligible for the study: 1. Signed written informed consent prior to any study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice. 2. Male or female patients aged ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Histologically confirmed adenocarcinoma of the colon or rectum with advanced or metastatic disease. 5. Patients whose disease has recurred or progressed during or after completion of at least one (1) standard regimen of cytotoxic agents. Patients may have had any number of prior regimens as long as the other entry criteria are met. Preferred patients are those who have progressed on first line FOLFIRI or FOLFOX with or without bevacizumab. Patients may have had prior exposure to monoclonal antibodies such as cetuximab, bevacizumab or panitumumab. 6. All clinically significant adverse events of any prior chemotherapy, surgery or radiotherapy must have resolved to CTCAE v3.0 grade ≤ 1. Neuropathy of CTCAE v3.0 grade ≤ 2 will be allowed but the neuropathy should be closely monitored throughout the trial. 7. A minimum of 4 weeks must occur between last receipt of chemotherapy, biotherapy, radiotherapy, or major surgery and registration. 8. Be willing and able to comply with the protocol for the duration of the study. 9. If prior malignancy was diagnosed, other than colorectal, no evidence of disease from that cancer, off all therapy for that cancer and recovered to grade 1 or less toxicity from prior treatment. Exclusion Criteria: Patients with any of the following will be excluded from participation in the study: Disease 1. Known central nervous system (CNS) metastases unless controlled for ≥ 4 months without the use of steroids. 2. Patients who are candidates for neoadjuvant "conversion" therapy followed by curative surgery. Prior Treatments 3. Prior pelvic irradiation. 4. Administration of any investigational agent (therapeutic or diagnostic), within 4 weeks prior to first study dosing. 5. Patients with a prior history of cetuximab hypersensitivity may be admitted to Part 1 of the study only. Other Concomitant Medications 6. Chronic oral or intravenous corticosteroids. (Note: Doses ≤ 5 mg/day of prednisone or equivalent are permitted. Topical, inhaled and intra-articular corticosteroids are allowed.) 7. Therapeutic anticoagulation (warfarin \> 1 mg/day or heparin). Low-dose warfarin for port prophylaxis and low-molecular weight heparin at therapeutic doses are allowed. Laboratory 8. The following laboratory results: * Hemoglobin \< 9.0 g/dL Absolute neutrophil count \< 1.5 x 109/L Platelet count \< 100 x 109/L * Total bilirubin \> 1.5 x upper limit of normal (ULN) * ALT or AST \> 2.5 x ULN (\> 5 x ULN if liver metastases present) * Alkaline phosphatase \> 2.5 x ULN (\> 5 x ULN if liver metastases present, or \> 10 x ULN in case of the presence of bone metastases) * Serum creatinine \> 1.5 x ULN * Albumin \< 2.5 g/dL Other Conditions or Procedures 9. Grade 3 or 4 non-hematological toxicity or febrile neutropenia related to previous irinotecan-based regimens. 10. Homozygous for the UGT1A1\*28 allele. 11. Known hypersensitivity to murine proteins or oligonucleotides. 12. Pregnant or breast-feeding women. 13. Women of childbearing potential with either positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. 14. Men or women of childbearing potential who refuse or who are unable to use an acceptable means of contraception during the study. 15. History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the Investigator to be clinically significant precluding informed consent or interfering with compliance. 16. Pre existing autoimmune or antibody-mediated diseases, including, but not limited to, the following: organ allografts, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome and autoimmune thrombocytopenia, known Gilbert's syndrome. 17. Signs/symptoms of bowel obstruction or pseudo-obstruction or history of inflammatory bowel disease. 18. Clinically significant (i.e., active) cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 6 months. 19. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs. 20. Serious uncontrolled concomitant disease, intercurrent infections, or other known medical conditions that in the opinion of the Investigator puts the patient at increased risk for significant toxicities from treatment, such as hypertension, uncontrolled by medication, chronic hepatitis (viral or other) or cirrhosis, known human immunodeficiency virus (HIV) infection, or uncontrolled diabetes. 21. Legal incapacity or limited legal capacity.