A Study in Second Line Metastatic Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Ramucirumab; Placebo; Irinotecan; Folinic Acid; 5-Fluorouracil
Intervention description: 8 milligrams / kilogram (mg/kg) administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision; Administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision; 180 milligrams/square meter (mg/m^2) administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision; 400 mg/m^2 administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision; 400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision
Intervention MeSH terms: Leucovorin; Folic Acid; Fluorouracil; Irinotecan; Ramucirumab; Levoleucovorin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1072.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: second line; metastatic colorectal cancer; FOLFIRI; ramucirumab; CRC; mCRC

Summary:

      The purpose of this study is to compare overall survival in participants with metastatic
      colorectal cancer treated with either ramucirumab and FOLFIRI or placebo and FOLFIRI.
    

Eligibility criteria:

        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)

          -  The participant has received first-line combination therapy of bevacizumab,
             oxaliplatin, and a fluoropyrimidine for metastatic disease and, a) Experienced
             radiographic disease progression during first-line therapy, or b) Experienced
             radiographic disease progression ≤6 months after the last dose of first-line therapy,
             or c) 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.
             Note that a participant must have received a minimum of 2 doses of bevacizumab as part
             of a first-line regimen containing chemotherapy; in addition, a participant must have
             received at least 1 cycle of first-line therapy that included bevacizumab, oxaliplatin
             and a fluoropyrimidine in the same cycle. Note that a participant 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 participants with rectal
             cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic
             regimen. Note that 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)).
             Participants 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, a Grade 3-4 bleeding event, or 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, or 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