This study is ongoing, but not recruiting participants

Inclusion Criteria:

• Histologically or cytologically confirmed colorectal cancer, excluding primary tumors of appendiceal origin (participants are eligible to enroll irrespective of KRAS mutation status)
• Confirmed metastatic colorectal cancer (Stage IV)
• Received first-line combination therapy of bevacizumab, oxaliplatin, and a fluoropyrimidine for metastatic disease and
  • Experienced radiographic disease progression during first-line therapy
  • Experienced radiographic disease progression ≤ 6 months after the last dose of first-line therapy
  • Discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression ≤ 6 months after the last dose of first-line therapy
  • Must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy
  • Must have received at least 1 cycle of first-line therapy that included bevacizumab, oxaliplatin and a fluoropyrimidine in the same cycle
  • Must not have received more than 2 different fluoropyrimidines as part of a first-line regimen
    • Disease progression is not an acceptable reason for discontinuing 1 fluoropyrimidine and starting a second fluoropyrimidine
• Receipt of no more than 2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted)
  • For rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen
  • Rechallenge with oxaliplatin is permitted and will be considered part of the first-line regimen for metastatic disease, both initial oxaliplatin treatment and subsequent rechallenge are considered as 1 regimen
• Measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Adequate hematologic, renal and hepatic function
• Adequate coagulation function [International Normalized Ratio (INR) ≤1.5 and Partial Thromboplastin Time (PTT) or activated PTT (aPTT) ≤1.5 x upper limit of normal (ULN)).
  • If on full-dose anticoagulation must be on a stable dose of anticoagulant therapy and if on oral anticoagulation, must have an INR ≤3 and have no clinically significant active bleeding or pathological condition that carries a high risk of bleeding
• Consent to provide a historical colorectal cancer tissue sample for assessment of biomarkers and the tumor tissue sample is available
• Ability to provide signed informed consent

Exclusion Criteria

• Receipt of bevacizumab ≤ 28 days prior to randomization
• Receipt of any investigational therapy for non-oncology clinical indication ≤ 28 days prior to randomization
• Receipt of any previous systemic therapy, other than a combination of bevacizumab, oxaliplatin, and a fluoropyrimidine, for first-line treatment of metastatic colorectal cancer
• Known leptomeningeal disease or brain metastases or uncontrolled spinal cord compression (currently or in the past)
• Experience of any arterial thrombotic or arterial thromboembolic events, including, but not limited to, myocardial infarction, transient ischemic attack, or cerebrovascular accident, ≤12 months prior to randomization
• Pregnant (confirmed by serum beta human chorionic gonadotropin (ß HCG) test ≤ 7 days prior to randomization) or lactating
• History of inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization
• Acute or subacute bowel obstruction or history of chronic diarrhea which is considered clinically significant in the opinion of the investigator
• Grade 3 or higher bleeding event ≤ 3 months prior to randomization
• Experience of any of the following during first-line therapy with a bevacizumab-containing regimen
  • An arterial thrombotic/thromboembolic event
  • Grade 4 hypertension
  • Grade 3 proteinuria
  • Grade 3-4 bleeding event
  • Bowel perforation
• Known history or clinical evidence of Gilbert's Syndrome, or is known to have any of the following genotypes
  • UGT1A1*6/*6
  • UGT1A1*28/*28
  • UGT1A1*6/*28
• Known allergy to any of the study treatment components, including any components used in the preparation of ramucirumab, or other contraindication to receive the study treatments
• Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinical meaningful ascites resulting from cirrhosis
  • Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis