A Study in Second Line Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-blind, Multicenter Phase 3 Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: Ramucirumab
* Biological: Placebo
* Drug: Irinotecan
* Drug: Folinic Acid
* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFIRI + Ramucirumab<br> | Biological: Ramucirumab<br>* 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<br>* Other names: IMC-1121B;Drug: Irinotecan<br>* 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<br>Drug: Folinic Acid<br>* 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<br>* Other names: leucovorin;Drug: 5-Fluorouracil<br>* 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<br>|
| Placebo Comparator: FOLFIRI + Placebo<br> | Biological: Placebo<br>* Administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision<br>Drug: Irinotecan<br>* 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<br>Drug: Folinic Acid<br>* 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<br>* Other names: leucovorin;Drug: 5-Fluorouracil<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time in months from the date of randomization to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last known date alive. | Randomization to Date of Death from Any Cause Up to 39.36 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Time | PFS was defined as the time from the date of randomization until the date of objectively determined progressive disease (PD) [according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1] or death due to any cause, whichever was first. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). Participants who died without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment. | Randomization to Measured PD or Date of Death from Any Cause Up to 38.01 Months | 
| Percentage of Participants Achieving an Objective Response (Objective Response Rate) | The objective response rate is equal to the proportion of participants achieving a best overall response of partial response or complete response (PR + CR). Response was defined using RECIST, v. 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameter. | Randomization until Disease Progression Up to 38.01 Months | 
| Change From Baseline in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 Global Health Status | The EORTC QLQ-C30 (v. 3.0) is a self-administered, cancer-specific questionnaire with multidimensional scales assessing 15 domains (5 functional domains, 9 symptoms, and global health status). A linear transformation was applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For the functional domains and global health status scale, higher scores represent a better level of functioning. For symptom scales, higher scores represent a greater degree of symptoms. Maximum improvement is the best post-baseline change. | Baseline Up to 171 Weeks | 
| Change From Baseline in EuroQol- 5D (EQ-5D) | The EQ-5D is a generic, multidimensional, health status instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). A negative change indicated a worsening of the participant's health status. | Baseline and 30-Day Follow-Up (FU) up to 171 Weeks | 
| Percentage of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | Blood samples were tested to determine if a participant reacted to ramucirumab by producing anti-ramucirumab antibodies. Samples were identified as treatment emergent anti-drug antibody (TE ADA) if the post-treatment sample had an increase of at least 4 fold in titer from pre-treatment values. If the pre-treatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence. The percentage of participants with TE ADA was calculated as: (the number of participants with TE ADA / total number of participants with at least 1 post-treatment immunogenicity sample analyzed)*100. | Cycles 1, 3, 5, and 30-Day FU | 
| Observed Maximum Concentration (Cmax) and Observed Minimum Concentration (Cmin) of Ramucirumab |  | Preinfusion and 1 hour postinfusion in Cycles 3, 5, 9, 13, and 17 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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second line, metastatic colorectal cancer, FOLFIRI, ramucirumab, CRC, mCRC