Colorectal Neoplasms

Inclusion Criteria

- Male or female subjects ≥18 years of age;
 - Histological or cytological confirmation of adenocarcinoma of the colon or/and rectum;
 - Subjects with metastatic colorectal cancer (CRC) whose disease progressed or who were intolerant to standard chemotherapy based on fluoropyrimidine, oxaliplatin, irinotecan, and an anti-EGFR therapy if RAS wild-type.  This progression must be during or within 4 months following the last administration of standard therapies.
 - Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, Version 1.1.  
 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
 - Adequate bone-marrow, liver, and renal function
 - Women of childbearing potential and men must agree to use adequate contraception when sexually active during the study and for at least 8 weeks after the last study drug administration.

Exclusion Criteria

- Prior treatment with an antiangiogenic agent;
 - Congestive heart failure of New York Heart Association (NYHA) class 2 or worse;
 - Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).  Myocardial infarction less than 6 months before start of study drug;
 - Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
 - Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management);
 - Ongoing acute or chronic infection (> Grade 2 NCI-CTCAE v 4.03);
 - Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication) events within 6 months of study enrollment.  Subjects being treated with low-weight heparin are allowed to participate as long as dose is limited to prophylactic use.  
 - Any history of or currently known brain metastases (head CT/MRI will be performed during screening period if brain metastases are suspected)
 - Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years before study entry, except for curatively treated cervical cancer in situ, in situ ductal breast cancer, non-melanoma skin cancer and superficial bladder tumors;
 - Last chemotherapy dose or any other anti-cancer therapy administered in less than 4 weeks from start of study treatment;
 - Use of therapeutic anticoagulation;
 - Proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (Grade 3, NCI-CTCAE v 4.03) on urinalysis screening result.  If there is medical history of proteinuria, previous urinalysis results should be considered and/or performed so at least 2 results separated by at least 2 weeks are available;
 - History of interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
 - Non-healing wound, non-healing ulcer, or non-healing bone fracture;
 - Subjects with evidence or history of any bleeding diathesis, irrespective of severity;
 - Any hemorrhage or bleeding event ≥ Grade 3 NCI-CTCAE v 4.03 within 4 weeks prior to the start of study medication;
 - Known history of human immunodeficiency virus (HIV) infection;
 - History of active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy; 
 - Pregnancy or breastfeeding.