FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820 as Second-Line Therapy in Patients With Locally Advanced or Metastatic Colorectal Cancer

Inclusion Criteria: Patients may be entered in the study only if they meet all of the following criteria: 1. Male or female patient greater than or equal to 18 years of age; 2. Histologically or cytologically confirmed nonresectable locally advanced or metastatic colorectal adenocarcinoma; 3. Patients must have failed a first-line chemotherapy regimen for nonresectable locally advanced or mCRC (first-line bevacizumab is allowed). Patients randomized to the Phase Ib portion can have up to 3 total prior regimens (including adjuvant therapy in addition to treatment for advanced disease); 4. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) criteria; 5. Life expectancy of \> 3 months; 6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1; 7. Patients must have adequate renal function as evidenced by serum creatinine \<2 mg/dL and creatinine clearance \>50 mL/minute per the Cockcroft and Gault formula; 8. Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) \>1.5 x 109/L, platelets \>100 x 109/L, hemoglobin \>9.0 g/dL (a hemoglobin \<9.0 g/dL at Screening is acceptable if it is corrected to \>9 g/dL by growth factor or transfusion prior to first dose); 9. Patients must have adequate liver function as evidenced by bilirubin \<1.5 times the upper limit of the normal range (ULN), and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \<3 X ULN (in the case of liver metastases, \<5 X ULN). If there are bone metastases, liver-specific alkaline phosphatase may be separated from the total and used to assess liver function instead of total alkaline phosphatase; 10. Blood pressure must be well-controlled (\<140/90 mmHg at screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy; 11. Male or female patients of child-producing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment; 12. Females of childbearing potential must have a negative serum pregnancy test; 13. Females may not be breastfeeding; and 14. Ability to understand and willingness to sign a written consent. Exclusion Criteria: Patients will not be entered in the study for any of the following reasons: 1. Received chemotherapy, targeted therapy, radiotherapy, surgery, immunotherapy, or treatment in another clinical study within the 30 days prior to commencing study treatment or have not recovered from side effects of all treatment-related toxicities to Grade \<1, except for peripheral neuropathy (Grade 1 and Grade 2 are permitted) and alopecia; 2. Previously received irinotecan or irinotecan derivatives; 3. Previously received anti-alpha 2 integrin therapy; 4. History of other malignancies except: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for \>5 years; 5. Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization; 6. Are currently receiving any other anticancer treatment; 7. Palliative radiotherapy is not permitted throughout the study period; 8. Serious non-healing wound, ulcer, or active bone fracture; 9. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for a major surgical procedure during the course of the study; 10. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication; 11. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association \[NYHA\] Grade \>2, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia); 12. Active hemoptysis (defined as bright red blood of 13. Current or recent use (within 7 days) of full-dose warfarin (except low-dose warfarin as required to maintain patency of preexisting, permanent indwelling IV catheters). For subjects receiving warfarin, International Normalization Ratio (INR) should be \<1.5. Patients may have prophylactic use of low molecular weight heparin, however therapeutic use of heparin or low molecular weight heparin is not acceptable; 14. History of bleeding diathesis or coagulopathy; 15. Any history of cerebral vascular accident, transient ischemic attack or ≥ Grade 2 peripheral vascular disease, unless they have had no evidence of active disease for at least 6 months prior to randomization; 16. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1, unless affected area has been removed surgically; 17. Patients with organ allografts requiring immunosuppression; 18. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or active hepatitis C positive; 19. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin; 20. Hypersensitivity to sulfonamide derivatives; or 21. Have any medical condition that would interfere with the conduct of the study.