A study for people with advanced colorectal cancer who have been treated with a specific chemotherapy regimen (Bevacizumab, Oxaliplatin, and a Fluoropyrimidine) which was ineffective in stopping the spread of the colorectal cancer. Study participants will receive a different chemotherapy regimen (Irinotecan, Folinic Acid, and 5-Fluorouracil) and be randomly and unknowingly assigned to also receive the study drug (ramucirimab) or a non-active compound (placebo).

Phase 1

• Conditions: Metastatic Colorectal Cancer; MedDRA version: 17.0Level: LLTClassification code 10010036Term: Colorectal carcinomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2010-021037-32-DE
• Lead Sponsor: Eli Lilly and Company Limited, Indianapolis

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2010-12-06
• Last Update Posted: 3 October 2016

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 1050

Inclusion Criteria

- Histologically or cytologically confirmed metastatic colorectal cancer excluding primary tumors of appendiceal origin (patients are eligible to enroll irrespective of KRAS mutation status)
- Confirmed metastatic colorectal cancer (Stage IV)
- The patient 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 within 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 within 6 months after the last dose of first-line therapy; Note that a patient must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy. In addition, a patient must have received at least 1 cycle of first-line therapy that included bevacizumab, oxaliplatin, and a fluoropyrimidine inthe same cycle. Note that a patient 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 one 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). Note that re-challenge with oxaliplatin is permitted and will be considered part of 1 first-line regimen for metastatic disease.
- Measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v. 1.1)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Adequate hematologic, renal, hepatic and coagulation function
- 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 472
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 578

Exclusion Criteria

- Receipt of bevacizumab within 28 days prior to randomization
- Receipt of any investigational therapy within 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
- Experience of any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 12 months prior to randomization
- Pregnant (confirmed by serum beta human chorionic gonadotropin [ß HCG] test within 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) in the 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 within 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
- The patient has:
? cirrhosis at a level of Child-Pugh B (or worse); or
? cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to compare overall survival (OS) in patients with metastatic colorectal carcinoma (CRC) when treated with FOLFIRI in combination with placebo versus FOLFIRI in combination with ramucirumab DP.;Secondary Objective: Secondary objectives are to compare FOLFIRI plus placebo treatment with FOLFIRI plus ramucirumab DP treatment for:<br>• progression-free survival (PFS)<br>• objective response rate (ORR)<br>• patient-reported outcome (PRO) measures (using European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and EuroQol EQ 5D)<br>• safety profile<br><br>In addition, secondary objectives include:<br>• assessment of anti-ramucirumab antibodies (immunogenicity)<br>• assessment of serum levels of ramucirumab<br><br>Other objective is:<br>- assessment of the association between biomarkers and clinical outcome.;Primary end point(s): overall survival;Timepoint(s) of evaluation of this end point: Baseline to date of death from any cause

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Progression-free survival time <br>Proportion of patients achieving an objective response <br>Change in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 <br>Incidence of anti-ramucirumab antibodies <br>Cmax and Cmin of ramucirumab <br>Change in EuroQol EQ-5D ;Timepoint(s) of evaluation of this end point: PFS: Baseline to measured progressive disease or date of death from any cause <br>ORR: Baseline, every 6 weeks through week 36, then every 12 weeks thereafter until disease progression <br>QLQ-C30: Every 2 cycles through cycle 14, then every 4 cycles<br>Incidence of anti-ramucirumab antibodies: Baseline, 30-day follow-up <br>Cmax and Cmin of ramucirumab: Baseline, pre- and post-infusions at cycles 3 and 5, and at 30-day follow-up <br>EuroQol EQ-5D: Every 2 cycles through cycle 14, then every 4 cycles