Study of CS-1008 in Combination With FOLFIRI in Patients Who Have Failed Other Treatments

Inclusion Criteria: * Histologically confirmed, metastatic CRC that has progressed after first-line standard therapy that was not irinotecan-based. * At least 18 years of age. * Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2. * Adequate organ and bone marrow function as evidenced by: * Hemoglobin \>= 9 g/dL * White blood cell count (WBC) \>= 3.0 x 109/L * Absolute neutrophil count (ANC) \>= 1.5 x 109/L * Platelet count \>= 100 x 109/L * Serum creatinine \< the upper limit of normal (ULN) * AST and alkaline phosphatase =\< 2.5 x ULN if without liver metastasis and =\< 5.0 x ULN if liver metastasis * Total bilirubin =\< ULN * Male and female subjects of reproductive potential must be willing to consent to using effective contraception while on treatment and for 3 months after the end of treatment. * Female subjects of childbearing potential must have a negative pregnancy test (serum or urine) result within 8 days before starting study treatment. * Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an IRB-approved ICF before performance of any study-specific procedures or tests. * At study centers located in the US, subjects must also sign a HIPAA authorization. * KRAS Mutant Exclusion Criteria: * Anticipation of a need for a major surgical procedure or radiotherapy (RT) during the study. * Treatment with chemotherapy, hormonal therapy, RT, minor surgery, or any investigational agent within 4 weeks before study enrollment. Treatment with nitrosoureas, mitomycin C, immunotherapy, biological therapy, or major surgery within 6 weeks before study enrollment. * First-line therapy for CRC that was irinotecan-based. * History of any of the following conditions within 6 months before study enrollment: * Myocardial infarction; * Severe/unstable angina pectoris; * Coronary/peripheral artery bypass graft; * New York Heart Association (NYHA) class III or IV congestive heart failure; * Cerebrovascular accident or transient ischemic attack; * Pulmonary embolism or other clinically significant thromboembolic event; or * Clinically significant pulmonary disease (eg, severe chronic obstructive pulmonary disease or asthma). * Clinically active brain metastasis (ie, untreated, still requiring therapy with steroids or RT, or with progression within 4 weeks after completion of RT); an uncontrolled seizure disorder; spinal cord compression; or carcinomatous meningitis. * History of malignancy other than CRC, unless there is the expectation that the malignancy has been cured, and tumor-specific treatment for the malignancy has not been administered within the previous 5 years. * Clinically significant active infection that requires antibiotic therapy or Human Immunodeficiency Virus (HIV)-positive subjects receiving antiretroviral therapy. * Previous treatment with CS-1008, other agonistic DRSantibodies, or with TRAIL agonists. * If female, pregnant or breastfeeding. * Known history of hypersensitivity reactions to any of the components of CS-1008, irinotecan, leucovorin, or 5-FU formulations. * Serious intercurrent medical or psychiatric illnesses or any other conditions that in the opinion of the Investigator would impair the ability to give informed consent or unacceptably reduce protocol compliance or safety of the study treatment. * Must not be known to be homozygous for the UGT1A1\*28 allele, as this increases the risk for neutropenia following irinotecan treatment. * Kras allele status must not be wild type. * Dihydropyrimidine dehydrogenase (DPD) deficiency.